cis-4-pyrrolidin-1-yl-L-proline: A highly stereoselective organocatalyst for the direct aldol reaction

Article abstract of DOI:10.1055/s-2006-951557

Modification of the pyrrolidinyl backbone of proline has not been quite successful for improving the catalytic efficiency and enantioselectivity. In this study, cis substitutions on the C4 position of proline with nitrogen-containing groups were found to

Full text of DOI:10.1055/s-2006-951557

LETTER
3319
cis-4-Pyrrolidin-1-yl-L-Proline: A Highly Stereoselective Organocatalyst for
the Direct Aldol Reaction
eaction ang,a,b Siyu Wei, Jian Sun*a
a
O
Y
rganocatalyst for
u
the
D
irect Aldol
R
W
a
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85222753; E-mail: sunjian@cib.ac.cn
b
Graduate School of Chinese Academy of Sciences, Beijing 100080, P. R. of China
Received 30 August 2006
HO
HO
R
NH
Abstract: Modification of the pyrrolidinyl backbone of proline has
not been quite successful for improving the catalytic efficiency and
enantioselectivity. In this study, cis substitutions on the C4 position
of proline with nitrogen-containing groups were found to have sig-
nificant impacts on both the reactivity and selectivity of the catalyst
for the direct aldol reaction of aromatic aldehydes with cyclohex-
anone. cis-4-Pyrrolidin-1-yl-L-proline exhibited dramatically im-
proved reactivity, diastereo- and enantioselectivity compared with
the parent L-proline, affording high isolated yields (up to 99%), ex-
cellent diastereoselectivities (>99:1 dr) and enantioselectivities
CO2H
CO2H
CO2H
CO2H
N
H
N
H
N
H
N
H
4a R = MeCO
4b R = PhCO
4c R = Ms
1
2
3
4d R = Ts
e R = p-NO2C6H4SO2
N
N
4
CO2H
2
CO H
N
H
N
H
(>99% ee). The presence of trifluoroacetic acid was found to be crit-
5
6
ical for the outstanding performance of this catalyst.
Key words: proline derivative, diastereoselectivity, enantioselec-
Figure 1
tivity, cyclohexanone, asymmetric direct aldol reaction
exhibiting significantly improved reactivity and stereose-
lectivity compared with the parent proline in the intermo-
lecular direct aldol reaction.8 In contrast, there have been
only a limited number of examples of proline-based cata-
lysts achieved through modification of the pyrrolidinyl
group that showed significantly improved catalytic effi-
ciency and enantioselectivity.1 In this context, we re-
cently became interested in designing and synthesizing
novel proline-based catalysts by modifying the pyrrolidi-
nyl group. Herein we present cis-4-pyrrodin-1-yl-L-pro-
line (5, Figure 1) as an excellent catalyst for the
asymmetric aldol reaction of aromatic aldehydes with cy-
clohexanone, affording high isolated yields (up to 99%),
excellent diastereoselectivities (>99:1 dr) and enantiose-
lectivities (>99% ee).
The aldol reaction is a fundamentally important carbon–
carbon bond-forming reaction and has been widely used
in organic synthesis. The development of catalytic asym-
,9
1
metric direct aldol reaction has attracted remarkable ef-
forts due to its outcome of chiral b-hydroxyl carbonyl
0,11
2
compounds and its atom economy. However, highly
efficient and enantioselective catalysts available for this
transformation were limited to biological macro-
3
4
molecules and a few of chiral organometallic complexes
before List, Barbas and coworkers recently reported a big
breakthrough that L-proline (1, Figure 1) could effectively
catalyze the enantioselective intermolecular direct aldol
5
reaction. Given the small size, the non-transition-metal
feature and the relative broad substrate spectrum of
proline, this catalyst system immediately attracted a great We were particularly interested in L-proline derivatives
deal of attention and subsequently stimulated intense with a cis 4-substituent on the pyrrolidine ring considering
interest in the development of novel proline-based chiral that these compounds could be easily prepared starting
6
–11
organocatalysts.
from the readily available trans-4-hydroxy-L-proline (2,
Figure 1). On the other hand, a cis 4-substituent should
The shortcomings of proline as catalyst for the intermo-
lecular direct aldol reaction include the high enantioselec-
tivity only for a limited range of substrates, the relatively
H2N
5
HO
low reactivity and the narrow solvent scope. To over-
come these shortcomings, one could consider the modifi-
cation of the carboxylic acid group and/or the pyrrolidinyl
group of proline. In the past several years, a number of
proline derivatives obtained through modifying the car-
boxylic acid group have emerged as excellent catalysts,
Ref. 12
1
. RCl, Et3N
CO2Me
4a–e
CO2H
N
N
H
2. LiOH
3. TFA
Boc
7
2
1. Br(CH2)4Br
. LiOH
. TFA
2
3
SYNLETT 2006, No. 19, pp 3319–3323
Advanced online publication: 23.11.2006
0
1
.1
2
.2
0
0
6
5
DOI: 10.1055/s-2006-951557; Art ID: W18106ST
Scheme 1
©
Georg Thieme Verlag Stuttgart · New York

3
320
Y. Wang et al.
LETTER
O
OH
O
O
catalyst (20 mol%)
r.t.
H
+
+
syn isomer
O2N
2
O N
8a
9
10a
Scheme 2
have better chances than a trans-4-substituent to have an Table 1 Screening of Catalysts in the Aldol Reaction of Cyclohex-
a
impact on the efficiency and stereoselectivity of the cata- anone with p-Nitrobenzaldehyde
lyst through steric and/or electronic interactions with the
b
d
Entry Catalyst
Additive
Yield (%) drc
ee (%)
transition state of the aldol reaction due to its proximity to
the stereogenic carboxylic acid group. Thus we prepared
a set of compounds bearing a cis 4-substituent (4a–e and
1
2
3
4
5
6
7
8
9
1
–
–
38
22
56
40
73
10
33
51
42
74
76
97
98
47
90
46:54
68 (83)
83 (94)
34 (55)
81 (93)
–8 (28)
64 (85)
50 (84)
64 (85)
30 (68)
28 (43)
16 (20)
97
2
48:52
65:35
44:56
57:43
40:60
46:54
57:43
54:46
50:50
49:51
88:12
93:7
5
, Figure 1) according to Scheme 1, including literature
1
2
steps, and tested their catalytic effects in the asymmetric
aldol reaction of p-nitrobenzaldehyde with cyclohex-
anone (Scheme 2). The trans isomer 6 was also synthe-
sized and tested for comparison (vide infra). As shown in
Table 1, when the reaction was performed in N,N-dimeth-
ylformamide at room temperature with catalysts 4a–e (20
mol%), the aldol product was obtained as a mixture of the
anti isomer 10a and the syn isomer in low to moderate
yields in 20 hours (entries 4–8). The resulting diastereose-
lectivities tend to be low; similar to those obtained with
catalysts 1–3 (entries 1–3). Catalyst 4a with a cis-4-acet-
3
4a
4b
4c
4d
4e
5
–
–
–
–
–
–
amido group afforded high ee values for both the syn and 10
anti products (93% and 81%, respectively, entry 4). In
comparison, the parent proline 1 afforded 83% and 68%
ee values (entry 1) and cis-4-hydroxy-L-proline 3 55% 12
and 34% ee values (entry 3) for the syn and anti products,
respectively, under identical conditions. Interestingly,
5
AcOH
PNBAe
D-CSA
TFA
–
1
1
5
5
1
3
5
97
catalyst 4b with a cis-4-benzoylamido group was found to 14
be much less enantioselective than its analogue 4a (entry
6
69:31
85:15
17 (17)
96
1
5
6
TFA
5
vs. 4), whereas the analogous catalysts 4c, 4d and 4e
a
b
c
with different cis-4-sulfonylamido groups exhibited simi-
larly moderate enantioselectivities (entries 6–8). These re-
sults clearly indicate that the cis 4-substituent has
dramatic impacts on the catalytic effects, which was fur-
ther supported by the behavior of catalyst 5. Bearing a cis-
Conditions: [8a] = 0.1 mol/L, solvent–cyclohexanone = 1:1, 20 h.
Isolated yield of mixture of anti/syn based on the aldehyde.
Diastereomeric ratio of anti/syn, determined by chiral-phase HPLC
analysis.
d
Enantiomeric excess of anti isomer, determined by chiral-phase
HPLC analysis; the data in parenthesis are for the syn isomer.
4
-pyrrolidin-1-yl group, catalyst 5 displayed disappoint-
e
Refers to para-nitrobenzoic acid.
ing reactivity and stereoselectivity under the testing con-
ditions. However, a completely different scenario was
observed when a Brønsted acid was added.
served with the trans isomer 6 (entries 14 and 15). Thus,
in the presence of TFA, both 5 and 6 could catalyze the
aldol reaction of 8a and 9 in high yield with excellent ste-
Considering that the strong basicity of the cis-4-pyrroli-
din-1-yl tertiary amino group might be the major culprit
for causing the decrease in the reactivity and stereoselec-
tivity of 5 compared with the other analogues, the effects
1
3
reoselectivity. As expected, the overall performance of
is better than that of its trans isomer 6 (entry 13 vs. 15).
5
of several Brønsted acids were examined with catalyst 5 To further optimize the reaction conditions, we examined
in the aldol reaction of 8a and 9 (entries 10–13, Table 1). the influences of different reaction parameters on the per-
While the weak acids in the same molar amount (20 formance of catalyst 5 in the aldol reaction of 8a and 9
mol%) as the catalyst were found to only have some pos- (Table 2). The solvent effects were first assessed. Al-
itive effects on the reactivity (entries 10 and 11), the reac- though dimethyl sulfoxide gave similar yield and enantio-
tivity, diastereo- and enantioselectivity were all selectivity value as N,N-dimethylformamide, the dia-
dramatically improved with the strong acids (entries 12 stereoselectivity obtained in dimethyl sulfoxide was sig-
and 13). In the presence of trifluoroacetic acid (TFA), the nificantly lower than in N,N-dimethylformamide (entry 2
5
-catalyzed reaction was completed in 20 hours in 98% vs. 1). The catalyst also performed well in chloroform and
yield with a diastereoselectivity of 93:7 and an enantio- dichloromethane (entries 3 and 4), affording high yields
meric excess of 97%. Similar effects of TFA were also ob- with slightly better diastereoselectivities and slightly
Synlett 2006, No. 19, 3319–3323 © Thieme Stuttgart · New York

LETTER
Organocatalyst for the Direct Aldol Reaction
3321
Table 2 Optimizing the Reaction Conditions for the Reaction of Cyclohexanone with p-Nitrobenzaldehyde Catalyzed by 5a
b
drc
d
Entry
Solvent
DMF
Temp (°C)
Time (h)
Yield (%)
ee (%)
1
r.t.
r.t.
r.t.
r.t.
r.t.
0
20
20
20
20
20
20
4
98
95
90
99
91
63
98
96
74
93:7
87:13
96:4
96:4
80:20
99:1
99:1
95:1
99:1
97
2
DMSO
CHCl3
CH Cl
97
3
95
4
95
2
2
5
THF
92
6
DMF
DMF
DMF
DMF
>99
>99
>99
>99
7e
8f
0
0
4
9g
0
27
a
Unless stated otherwise, conditions: [8a] = 0.1 mol/L, catalyst (20 mol%) and TFA (20 mol%), solvent–cyclohexanone = 1:1.
Isolated yield of mixture of anti/syn based on the aldehyde.
Diastereomeric ratio of anti/syn, determined by chiral-phase HPLC analysis.
b
c
d
e
f
Enantiomeric excess of anti isomer, determined by chiral-phase HPLC analysis.
[
8a] = 0.5 mol/L.
[
8a] = 0.5 mol/L; H O (1.0 equiv) was added.
2
g
[
8a] = 0.5 mol/L; H O (5.0 equiv) was added.
2
lower enantioselectivities than in N,N-dimethylform- Other aldehydes (Figure 2) were also examined to expand
amide. Tetrahydrofuran proved to be inferior (entry 5). the substrate scope of catalyst 5 under the optimal condi-
Next, with N,N-dimethylformamide as the solvent, we tions.1 As shown in Table 3, all the selected aromatic
examined the effects of the temperature and the reaction aldehydes afforded excellent diastereoselectivities and
concentration. When the temperature was lowered from enantiomeric excess values. High yields of over 90% were
room temperature to 0 °C, excellent diastereoselectivity obtained for benzaldehydes 8a–g bearing an electron-
5,16
(
(
99:1 dr) and enantioselectivity (>99% ee) were obtained withdrawing group on the benzene ring (entries 1–7). For
entry 6). However, the reaction was significantly slowed the relatively electron-rich aldehydes 8h–k, difficult sub-
down, affording only 63% yield in 20 hours. Gratifyingly, strates for all the currently available organocatalysts,17
when the concentration of aldehyde 8a was increased moderate yields ranging from 28% to 81% were achieved
from 0.1 M to 0.5 M, the reaction became much faster and (entries 8–11). Furthermore, the heteroaromatic alde-
went to completion in four hours with a high yield of 98%, hydes 8l–n also reacted well to yield the aldol products in
whereas the excellent diastereoselectivity and enantio- high yields and excellent diastereo- and enantioselectivi-
selectivity were not affected at all (entry 7). In addition, ties (entries 12–14). The limitation of catalyst 5 is its inef-
water was examined as an additive, which proved to be fectiveness for the aliphatic aldehydes.18
unfavorable to the reactivity and diastereoselectivity
In summary, we have developed highly efficient stereose-
1
4
(
entries 8 and 9).
lective new catalysts for the direct aldol reaction through
the introduction of nitrogen-containing substituents on the
cis 4-position of proline. cis-4-Pyrrolidin-1-yl-L-proline
catalyzed the aldol reaction of cyclohexanone with a
broad range of aromatic aldehydes, including heteroaro-
matic aldehydes, with high isolated yields and excellent
diastereoselectivities and enantioselectivities. The pres-
ence of trifluoroacetic acid was found to be critical for the
outstanding performance of this catalyst system.
O
O
H
H
N
R
8
a R = p-NO2, 8b R = m-NO2, 8c R = o-NO2
d R = p-Cl, 8e R = o-Cl, 8f R = p-Br
g R = p-CN, 8h R = H, 8i R = p-Me
j R = p-OMe, 8k R = m-OMe
8l
8
8
8
O
O
Acknowledgment
N
S
H
H
We are grateful for financial support from National Natural Science
Foundation of China (Project 20402014) and from the Chinese
Academy of Sciences (Hundred of Talents Program).
N
8m
8n
Figure 2
Synlett 2006, No. 19, 3319–3323 © Thieme Stuttgart · New York

3
322
Y. Wang et al.
LETTER
Table 3 Aldol Reactions of Cyclohexanone with Various Alde-
hydes Catalyzed by 5
(6) For reviews, see: (a) List, B. Acc. Chem. Res. 2004, 37, 548.
(b) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
a
(
2
c) Notz, W.; Tanaka, F.; Barbas, C. F. III Acc. Chem. Res.
004, 37, 580. (d) List, B. Tetrahedron 2002, 58, 5573.
O
OH
O
O
5
(20 mol%), TFA
°C, DMF
R1
(e) Alcaide, B.; Almendros, P. Angew. Chem. Int. Ed. 2003,
42, 858. (f) Kazmaier, U. Angew. Chem. Int. Ed. 2005, 44,
+
+ syn isomer
R1
H
0
2
186.
8
9
10
(
7) For proline catalysis in the asymmetric intermolecular direct
aldol reactions, see the other leading references:
Entry
Aldehyde Time (h) Yield (%)b
drc
99:1
99:1
>99:1
96:4
>99:1
98:2
98:2
97:3
97:3
95:5
98:2
98:2
94:6
97:3
ee (%)d
>99
99
(
1
a) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305,
752. (b) Northrup, A. B.; MacMillan, D. W. C. J. Am.
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
4
11
18
40
24
72
10
72
72
72
32
4
99
94
90
94
99
92
96
81
43
28
69
93
86
50
Chem. Soc. 2002, 124, 6798. (c) Cordova, A.; Notz, W.;
Barbas, C. F. III J. Org. Chem. 2002, 67, 301. (d) Bøgevig,
A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem.
Commun. 2002, 620. (e) Casas, J.; Engqvist, M.; Ibrahem,
I.; Kaynak, B.; Cordova, A. Angew. Chem. Int. Ed. 2005, 44,
>99
>99
>99
>99
>99
99
1343. (f) Enders, D.; Grondal, C. Angew. Chem. Int. Ed.
2005, 44, 1210.
(
8) For selected examples, see: (a) 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. (b) Tang, Z.; Yang, Z.
H.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Org. Lett.
8g
8h
8i
2004, 6, 2285. (c) Mase, N.; Tanaka, F.; Barbas, C. F. III
Angew. Chem. Int. Ed. 2004, 43, 2420. (d) Torii, H.;
Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem. Int. Ed. 2004, 43, 1983. (e) Halland, N.; Braunton,
A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 4790. (f) Berkessel, A.; Koch, B.;
Lex, J. Adv. Synth. Catal. 2004, 346, 1141. (g) Tang, Z.;
Yang, Z. H.; Chen, X. H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.;
Gong, L. Z. J. Am. Chem. Soc. 2005, 127, 9285.
99
1
1
1
1
0
1
2
3
4
8j
97
8k
8l
99
98
(
h) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.;
8m
8n
8
97
Wennemers, H. Org. Lett. 2005, 7, 1101. (i) Chen, J.; Lu,
H.; Li, X.; Cheng, L.; Wan, J.; Xiao, W. Org. Lett. 2005, 7,
1
72
97
4543. (j) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C. Org. Lett.
a
Conditions: [8] = 0.5 mol/L, TFA (20 mol%), solvent–cyclo-
2005, 7, 5321. (k) Wang, W.; Li, H.; Wang, J. Tetrahedron
Lett. 2005, 46, 5077. (l) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84. (m) Gryko, D.; Lipinski, R. Adv. Synth.
Catal. 2005, 347, 1948. (n) Tang, Z.; Cun, L. F.; Cui, X.;
Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Org. Lett. 2006, 8, 1263.
hexanone = 1:1.
b
Isolated yield of mixture of anti/syn based on the aldehyde.
Diastereomeric ratio of anti/syn, determined by chiral-phase HPLC
c
analysis.
d
Enantiomeric excess of anti isomer, determined by chiral-phase
HPLC analysis.
(
o) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006, 128,
34.
7
References and Notes
(
9) For the work done in this lab, see: (a) Cheng, C.; Sun, J.;
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Commun. 2006, 215. (b) Cheng, C.; Wei, S.; Sun, J. Synlett
(
1) (a) Kim, B. M.; Williams, S. F. In Comprehensive Organic
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Aldol Reactions, Vol. 1–2; Mahrwarld, R., Ed.; Wiley-VCH:
Weinheim, 2004.
2
006, 2419.
10) (a) Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal.
001, 343, 171. (b) Benaglia, M.; Cinquini, M.; Cozzi, F.;
Puglisi, A.; Celentano, G. Adv. Synth. Catal. 2002, 344,
33. (c) Calderon, F.; Fernandez, R.; Sanchez, F.;
Fernandez-Mayoralas, A. Adv. Synth. Catal. 2005, 347,
(
(
2
(
(
(
2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M.
Angew. Chem. Int. Ed. 1995, 34, 259.
3) See review: Machajewski, T. D.; Wong, C.-H. Angew.
Chem. Int. Ed. 2000, 39, 1352.
4) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki,
M. Angew. Chem. Int. Ed. 1997, 36, 1871. (b) Yoshikawa,
N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1999, 121, 4168. (c) Trost, B. M.; Ito, H. J.
Am. Chem. Soc. 2000, 122, 12003.
5
1395. (d) Bellis, E.; Kokotos, G. J. Mol. Catal. A: Chem.
2005, 241, 166.
11) (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.;
Urushima, T.; Shoji, M.; Hashizume, D.; Koshino, H. Adv.
Synth. Catal. 2004, 346, 1435. (b) Bellis, E.; Kokotos, G.
Tetrahedron 2005, 61, 8669. (c) Hayashi, Y.; Sumiya, T.;
Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem. Int. Ed. 2006, 45, 958. (d) Itagaki, N.; Kimura, M.;
Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005, 7, 4185.
12) Abraham, D. J.; Mokotoff, M.; Sheh, L.; Simmons, J. E. J.
Med. Chem. 1983, 26, 549.
(
5) (a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2
000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F. III J. Am. Chem. Soc. 2001, 123, 5260.
c) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(
(
(
13) Significant beneficial effects of strong acid on the
enantioselectivity of proline for the same reaction has been
previously observed when water was used as the co-solvent,
Synlett 2006, No. 19, 3319–3323 © Thieme Stuttgart · New York

LETTER
in which case, however, no obvious improvements of the
Organocatalyst for the Direct Aldol Reaction
3323
was further purified through recrystallization from MeOH to
give the final product (0.65 g, 52% yield).
moderate reactivity and diastereoselectivity were achieved,
see: Wu, Y.-S.; Chen, Y.; Deng, D.-S.; Cai, J. Synlett 2005,
2
5
Compound 5: White solid; mp 232–236 °C; [a] –56.0
D
1
1627.
(c = 0.1, H O). H NMR (600 MHz, D O): d = 1.75 (m, 5 H),
2
2
(
14) Water has recently been demonstrated to be an excellent
additive or solvent for the organocatalytic asymmetric aldol
reactions, see refs. 8b, 8o and 11c.
2.50 (m, 1 H), 2.78 (br s, 4 H), 3.02 (dd, J = 7.1, 10.6 Hz, 1
1
3
H), 3.27–3.32 (m, 2 H), 3.80 (t, J = 8.6 Hz, 1 H). C NMR
(150 MHz, D O): d = 22.8, 33.9, 48.3, 52.8, 60.5, 63.7,
2
+
(
15) Procedure for the Preparation of (2S,4S)-4-Pyrrolidin-1-
176.6. HRMS (ESI): m/z [M + Na ] calcd for C H N O :
9
16
2
2
ylproline (5): To a solution of Et N (11.2 mL, 80.5 mmol)
207.1104; found: 207.1091.
3
and (2S,4S)-1-(tert-butoxycarbonyl)-4-aminoproline methyl
ester (7; 4.9 g, 20 mmol) in DMF (200 mL) was added 1,4-
dibromobutane (4.8 mL, 40.5 mmol). The mixture was
stirred at 60 °C for 4 h, and then cooled to 0 °C. Sat. aq
(16) General Procedure for the Aldol Reaction of Aldehydes
with Cyclohexanone: To a mixture of cyclohexanone
(0.2 mL) in DMF (0.2 mL) was added catalyst (0.04 mmol,
20 mol%) and TFA (0.04 mmol, 20 mol%). After stirring at
0 °C for 1 h, aldehyde (0.2 mmol) was introduced. The
reaction mixture was stirred at the same temperature for
solution of NaHCO was added, followed by addition of
3
EtOAc. The organic layer was separated and the aqueous
layer was extracted with EtOAc. The combined extracts
were washed with brine and dried over anhyd Na SO . After
1–72 h and was quenched with sat. aq NH Cl. EtOAc was
4
added to dilute the mixture. The organic layer was separated,
2
4
evaporation of the solvents under reduced pressure, the
residual yellow oil was purified by flash chromatography on
silica gel (eluent: hexane–EtOAc, 3:1) to give pure (2S,4S)-
washed with brine, dried over anhyd MgSO and
4
concentrated under reduced pressure. The residue was
purified through column chromatography on silica gel
(eluent: hexane–EtOAc, 3:1) to yield the corresponding
aldol products for further analysis.
1-(tert-butoxycarbonyl)-4-pyrrolidin-1-ylproline methyl
ester (3.5 g, 59%).
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-
pyrrolidin-1-ylproline methyl ester (2.0 g, 6.7 mmol) in
THF–H O (1:1, 20 mL) was added LiOH·H O (0.85 g, 20
(17) See references 8i, 8o, 9b, and 11c. See also: (a) Cordova,
A.; Zhou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.
Chem. Commun. 2005, 3586. (b) Zhou, W.; Ibrahem, I.;
Dziedic, P.; Sunden, H.; Cordova, A. Chem. Commun. 2005,
4946.
(18) It should be noted that when acetone was used as the donor
for the aldol reaction of aromatic aldehydes, catalyst 5
showed no obvious advantage over the parent L-proline in
terms of either the enantioselectivity or the reactivity.
2
2
mmol). The mixture was stirred at r.t. for 4 h and then
concentrated under reduced pressure. The resulting mixture
was treated with a mixture of TFA–CH Cl (1:2, 20 mL).
2
2
After stirring for 4 h, the reaction mixture was concentrated
under reduced pressure. The residue was subjected to
+
chromatography on a H ion-exchange resin column with
NH ·H O (3.0 M) as eluent to give a crude product, which
3
2
Synlett 2006, No. 19, 3319–3323 © Thieme Stuttgart · New York