Methyl 12-[d-prolinoylamino]cholate as a versatile organocatalyst for the asymmetric aldol reaction of cyclic ketones

Article abstract of DOI:10.1016/j.tetasy.2007.11.023

The use of cholic acid derivative 1, bearing a d-prolinamide moiety linked at the 12-position of cholic acid methylester, as an organocatalyst in the asymmetric aldol reaction of cyclic ketones and aromatic aldehydes, gave the corresponding aldol products in good yield and ee up to 98%. This organocatalyst has proven to be efficient both in water and in organic solvent, where it has been used with a 1% loading.

Full text of DOI:10.1016/j.tetasy.2007.11.023

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2894–2900
Methyl 12-[D-prolinoylamino]cholate as a versatile organocatalyst
for the asymmetric aldol reaction of cyclic ketones
a,b
Gian Luigi Puleo and Anna Iuliano
b,
*
a
Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56126 Pisa, Italy
Dipartimento di Chimica e Chimica Industriale, Universit a` di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
b
Received 9 October 2007; accepted 19 November 2007
Abstract—The use of cholic acid derivative 1, bearing a D-prolinamide moiety linked at the 12-position of cholic acid methylester, as an
organocatalyst in the asymmetric aldol reaction of cyclic ketones and aromatic aldehydes, gave the corresponding aldol products in good
yield and ee up to 98%. This organocatalyst has proven to be efficient both in water and in organic solvent, where it has been used with a
1
% loading.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
of water as a solvent requires the presence of acid or salt
additives in order for the organocatalyst to be efficient,
5
1
Since the seminal paper of List et al. demonstrated that
proline and proline analogues promote the asymmetric
direct aldol reaction with good enantioselectivities, several
efforts have been directed towards the synthesis of different
organocatalytic systems able to afford high levels of asym-
metric induction in this reaction. The formation of C–C
bonds via diastereoselective and enantioselective ways
or that a large excess of the donor carbonyl compound is
6
mandatory to perform the reaction. In addition, it is diffi-
cult to find an organocatalytic system that works both in
water and in organic solvents, conditions that would
permit a wider applicability of the chiral auxiliary.
We have recently synthesised a new family of asymmetric
organocatalysts, by linking the prolinamide moiety to the
different functionalised positions of cholic and deoxycholic
2
to afford products having both keto and hydroxyl groups,
easily explains the interest towards the asymmetric aldol
reaction. In addition, the organocatalytic version of this
chemical transformation offers the advantage of being envi-
ronmentally friendly, since no metal species are involved,
and the reaction can be performed without the use of an
7
acids. The preliminary study aimed at verifying the capa-
bility of these systems to work as organocatalysts in the di-
rect asymmetric aldol reaction between acetone and 4-
nitrobenzaldehyde showed that the best combination posi-
tion on the cholestanic backbone-absolute configuration
of the prolinamide moiety is obtained when the D-prolin-
amide unit is linked at the 12-position of the bile acids; in
addition, the presence of free hydroxyl groups at the 3-
and 7-positions guaranteed the achievement of good levels
3
inert atmosphere or absolute solvents. These last consider-
ations have prompted scientists to search for organocata-
lytic systems that can work under very environmentally
benign conditions, that is, low catalyst loading or using
water as reaction solvent. Many efforts have been
addressed towards the synthesis of such appealing organo-
catalysts that have produced systems able to afford very
7
of asymmetric induction. Indeed, derivative 1 (Fig. 1),
possessing these structural features, emerged as the best
4
7
good stereoselectivities under such type of conditions.
asymmetric organocatalyst, giving ees up to 80%. Its
However, the achievement of a versatile organocatalyst,
able to work with low catalyst loading or in water still
remains a challenge. In fact, it often happens that the use
effectiveness is attributable to the unique structure of cholic
acid, which gives rise, with the appended proline moiety, to
a chiral cavity, where the position of the aldehyde substrate
7
is controlled by the free hydroxyl groups.
*
Corresponding author. Tel.: +39 0502219231; fax: +39 0502219260;
e-mail: iuliano@dcci.unipi.it
These encouraging results prompted us to extend the use of
this organocatalyst to the reaction of other substrates and
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.023

G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 18 (2007) 2894–2900
2895
The use of a 1:2 H O/DMF mixture, the solvent giving the
best result with acetone as the donor substrate, with a 5%
2
HN
O
7
catalyst loading at room temperature and using only a two-
fold excess of ketone, afforded complete conversion of the
aldehyde substrate in 24 h (entry 1). The aldol product was
obtained with low diastereoselectivity in favour of the anti-
isomer, which showed a 77% ee (entry 1). Lowering the
temperature to 0 °C (entry 2) caused an improvement of
both diastereoselectivity, which went to 80%, and enanti-
oselectivity of the anti-isomer, which was obtained in
87% ee. This good result was flanked by a slowing down
of the reaction rate, with 70% of substrate conversion being
obtained. Further lowering of the reaction temperature to
ꢀ20 °C (entry 3) slightly improved both the diastereoiso-
meric and enantiomeric excesses, but slowed down the
reaction rate so that only a 50% conversion was obtained
in 24 h. Screening of various organic solvents (entries 4–
8) showed that the best results in terms of conversion of
the substrate as well as stereoselectivity were obtained
when non-competing hydrogen bonding solvents, such as
toluene, nitrobenzene or dichloromethane, were used. As
a matter of fact, the use of methanol, a protic solvent,
caused a decrease in both conversion and asymmetric
induction (entry 4). It is also noteworthy that toluene, a
p-rich aromatic solvent, and nitrobenzene, a p-acceptor
aromatic solvent, gave the same results, allowing us to con-
clude that no p–p stacking between solvent molecules and
aldehyde substrate was involved in determining the out-
come of the reaction. It seems likely that the organic sol-
vent only acts as a diffusion medium, when it cannot
interact with the substrate or the organocatalyst by means
of hydrogen bonds. As a matter of fact, worsening of the
O
NH
OMe
HO
OH
1
Figure 1. Chemical structure of organocatalyst 1.
to verify the possibility of performing the reaction using
water as solvent and low catalyst loading. Herein, we
report the results obtained using 1 as an organocatalyst
in the asymmetric direct aldol reaction of cyclic ketones
and various aromatic aldehydes, the evaluation of its effec-
tiveness both in organic solvents and in water, as well as
the possibility of performing the reaction with very low cat-
alyst loading.
2
. Results and discussion
The reaction between cyclohexanone and 4-nitrobenzalde-
hyde, using 1 as an organocatalyst, was performed accord-
ing to the ‘pre-activation’ method, which involves the
mixing of the ketone and 1 at reaction temperature for 1
8
hour, followed by the addition of the aldehyde. The effect
of different reaction parameters, such as solvent, catalyst
loading, amount of ketone and temperature, was investi-
gated and the results are reported in Table 1.
a
Table 1. Reaction of 4-nitrobenzaldehyde with cyclohexanone in the presence of organocatalyst 1
O
O
O
OH
a
H
+
NO2
NO2
c
c
b
Entry
Cat. (%)
Solvent
Temp (°C)
rt
Time (h)
Conv. (%)
de (%) (anti)
ee (%)
d
d
d
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
5
5
2
5
2
1
5
H
2
H
2
H
2
O/DMF
O/DMF
O/DMF
24
24
24
24
24
24
24
24
48
96
96
48
48
48
>98
70
50
46
28
28
80
82
82
83
83
84
84
80
85
95
92
94
46
77
87
90
63
87
85
86
86
81
68
68
87
87
0
ꢀ20
MeOH
DMF
Toluene
0
0
0
0
0
0
0
0
0
97
Nitrobenzene
>98
>98
61
31
12
>98
>98
>98
DCM
e
H
2
H
2
H
2
O
O
O
e
e
10
11
12
13
14
f
DCM
DCM
0
0
d
g
H
2
O/DMF
60
a
Reagents and conditions: p-nitrobenzaldehyde (0.25 mmol), cyclohexanone (0.5 mmol), catalyst, solvent (usually 0.5 mL); reactions were monitored by
TLC.
b
c
d
e
f
Determined by HPLC on chiral stationary phase (Chiralpack AS, hexane/2-propanol 85:15, 1 mL/min, 254 nm); main diastereoisomer was anti.
Determined by H NMR.
1
H
2
O/DMF 1:2.
All these reactions were performed in 2 mL of H
equiv of ketone was used.
2
O.
1
g
Organocatalyst with L-Pro was used; the opposite enantiomer was obtained in prevalence.

2896
G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 18 (2007) 2894–2900
reaction outcome occurs using a protic solvent (DMF,
entry 5, caused only slowing down of the reaction rate),
probably because the hydrogen bonds between the solvent
and aldehyde substrate or organocatalytic species compete
with the hydrogen bonds between the reactive enamine
species of the organocatalyst and the aldehyde, which are
believed to be important for the stereoselectivity of the
was obtained in prevalence: this result suggests that the
sense of asymmetric induction is governed by the proline
moiety linked to the 12-position of the cholic acid.
The conditions giving the best results in the asymmetric
aldol reaction of cyclohexanone and 4-nitrobenzaldehyde,
that is, water with 5% catalyst loading and dichloromethane
with 1% of 1 at 0 °C, were used to test the reaction with
other substrates. The results concerning the aldol reaction
of cyclohexanone and various aromatic aldehydes are
reported in Table 2. The reactions carried out in water
(entries 1–6) were faster than those performed in dichloro-
methane (entries 7–11) independently of the aldehyde
substrate. This can be attributed mainly to the different
catalyst loading that has a scarce influence in the case of
the reaction of 4-nitrobenzaldehyde but affects to a
greater extent the reaction of other kind of aldehyde
substrates.
9
reaction. Water behaved in a different way (entry 9):
although the reaction was slower, when performed in pure
water as a solvent, a good level of asymmetric induction
was obtained. This is not surprising if we take into account
that water does not solubilise either the reagents or organ-
ocatalysts. The hydrophobic components are obliged by
1
0
water to react in a ‘concentrated organic medium’: in this
sense water does not compete for hydrogen bonds, behav-
ing as, for example, dichloromethane and guarantees the
achievement of good ees. Decreasing the catalyst loading
or ketone amount had a detrimental effect on both the
reaction rate and the asymmetric induction (entries 10
and 11). Conversely, lowering of the catalyst loading in
dichloromethane solution did not affect the extent of the
asymmetric induction, or the reaction rate (entries 12 and
The extent of the substrate conversion depended on the
electrophilic character of the aromatic aldehyde as well as
the steric hindrance near the carbonyl group in both the
solvents: as a matter of fact that benzaldehyde and 2-nitro-
benzaldehyde gave a lower conversion (entry 5) or required
longer reaction times to afford good conversions (entries 6,
10 and 11). Only 4-chlorobenzaldehyde, an electrophilic
and unhindered substrate, exhibited an unusual behaviour
(in water), giving a 58% conversion (entry 2). Both the dia-
stereomeric and enantiomeric ratios were affected by the
solvent in an opposite way: water gave very high diastereo-
isomeric excess in favour of anti-diastereoisomer (entries 1–
6), whereas the highest enantiomeric excesses were
obtained by performing the reaction in dichloromethane
solution (entries 7–11). The extent of asymmetric induction
depended on the nature of the aldehyde substrate to a
1
3). The aldol reaction between 4-nitrobenzaldehyde
and cyclohexanone can be carried out using a very low
amount of 1 (1%), without a loss in catalytic efficiency
or asymmetric induction: in addition, the low catalyst load-
ing had a positive effect on the diastereoselectivity of the
reaction, with the aldol product being obtained in 94% de
(
entry 13). The use of the diastereoisomeric analogue of
1
, which possesses an L-prolinamide moiety linked at the
1
2-position of cholic acid, gave the aldol product in high
yield but in lower enantiomeric excess (entry 14), suggest-
ing that the more effective diastereoisomer is obtained
when the D-proline moiety is linked at the 12-position of
cholic acid. The opposite enantiomer of the anti-product
a
Table 2. Reaction of aromatic aldehydes with cyclohexanone in the presence of organocatalyst 1
O
O
O
OH
Ar
a
H
Ar
+
c
c
b
Entry
Ar
Solvent
Catalyst (mol %)
Time (h)
Conv. (%)
de (%)
ee (%)
d
d
d
d
d
d
f
1
2
3
4
5
6
7
8
9
4-FC
6
H
4
H
H
H
H
H
H
2
2
2
2
2
2
O
O
O
O
O
O
5
5
5
5
5
5
1
1
1
1
1
48
48
48
48
48
95
58
>98
93
46
61
>98
80
74
76
81
94
84
97
95
99
80
80
83
85
95
26
81
f
4-ClC
4-CF
2-ClC
6
H
4
68
g
3
C
6
H
4
63
62
62
80
h
6
H
4
g
2-NO
Ph
2
C
6
H
4
h
72
e
e
e
e
e
f
4-FC
6
H
4
DCM
DCM
DCM
DCM
DCM
120
120
48
120
120
80
f
4-ClC
6
H
4
90
g
4-CF
2-NO
Ph
3
C
6
H
4
84
80
80
g
1
1
0
1
2
C
6
H
4
h
a
b
c
Reagents and conditions: aldehyde (0.25 mmol), cyclohexanone (0.5 mmol), catalyst, solvent at 0 °C.
Enantiomeric excess of the anti = diastereoisomer.
Determined by H NMR; main diastereoisomers were anti.
All these reactions were performed in 2 mL of H O.
2
All these reactions were performed in 0.5 mL of DCM.
Determined by HPLC analyses on Chiralpack AD, 254 nm, hexane/2-propanol 90:10, 0.5 mL/min.
Chiralcel OD-H, 254 nm, hexane/2-propanol 95:5, 1 mL/min.
Chiralcel OD-H, 210 nm, hexane/2-propanol 99:1, 0.4 mL/min.
1
d
e
f
g
h

G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 18 (2007) 2894–2900
2897
greater extent in water than in dichloromethane: aldehyde
possessing a less polarisable aromatic ring gave the highest
enantiomeric excess in water (entries 1 and 6), whereas the
ees in dichloromethane were around the 80% value (entries
formed in dichloromethane gave a prevalence of the anti-
diastereoisomer, except when 2-nitro and 2-chlorobenz-
aldehyde were used as substrates, suggesting that ortho-
substitution is a structural feature that helps the formation
of the syn-isomer. In contrast, when water was used as
reaction solvent, prevalence of the syn-isomer was ob-
tained, apart from the reaction of benzaldehyde (entry
12) that still gave a prevalence of the anti-isomer, but to
a remarkably lower extent. These results suggest that water
can stabilise the transition state leading to the formation of
the syn-product: such a kind of stabilisation gives rise to
inversion of the diastereoisomeric ratio (entries 8–11), or
to a lower prevalence of the anti-product (entry 12) or to
a higher prevalence of the syn-isomer (entries 13 and 14),
in passing from dichloromethane to water. The anti-prod-
ucts were obtained in good enantiomeric excesses in both
solvents, apart from the reactions of 2- and 4-chlorobenz-
aldehyde in water (entries 10 and 14): as observed in the
case of cyclohexanone, the best asymmetric inductions
were achieved when the reaction was performed in dichlo-
romethane (entries 1–7). On the contrary, the enantiomeric
excesses of the syn-products were lower and a general trend
depending on the solvent cannot be found: the syn-product
coming from the reaction of benzaldehyde was obtained in
62% ee in dichloromethane (entry 5), whereas a 60% ee of
the syn-product coming from the reaction of 4-nitrobenz-
aldehyde was obtained in water (entry 8). The sense of
asymmetric induction, as far as the anti-product was con-
cerned, changed in passing from dichloromethane to water
7
, 9–11) except for 4-chlorobenzaldehyde, which afforded
the aldol product in 90% ee (entry 8).
The same conditions were used in the aldol reaction of
cyclopentanone and various aromatic aldehydes: the results
are reported in Table 3.
The conversions of the aldehyde substrates were similar in
water and in dichloromethane, except for 2-chlorobenz-
aldehyde, 4-chlorobenzaldehyde and 4-nitrobenzaldehyde,
which gave remarkably higher conversions in water (entries
8
, 10 and 14).
Conversions with this ketone also depended on the elec-
tronic nature of the aldehyde as well as on the steric hin-
drance near the carbonyl group (entries 5–7 and 12–14),
with the sole exception of the reaction of 4-nitrobenzalde-
hyde in dichloromethane (entry 1).11 As far as the dia-
stereoisomeric ratios are concerned, low diastereoisomeric
prevalence was observed in all the cases: this is not surpris-
ing, given that the use of cyclopentanone as a donor
1
2
substrate usually affords low diastereoisomeric excesses.
However, it should be noted that in most cases the dia-
stereoisomeric ratios are higher than those reported with
1
2
other proline-derived organocatalysts. The reactions per-
a
Table 3. Reaction of aromatic aldehydes with cyclopentanone in the presence of organocatalyst 1
OH
Ar
O
O
O
a
H
Ar
+
c
c
b
b
Entry
Ar
Solvent
Catalyst (mol %)
Conv. (%)
dr (%) (anti:syn)
er (%) (anti)
er (%) (syn)
d
g
g
1
2
3
4
5
6
7
8
9
0
1
2
3
4
4-NO
2
C
6
H
4
DCM
1
1
1
1
1
1
1
5
5
5
5
5
5
5
36
>98
83
>98
93
69:31
53:47
54:46
69:31
72:28
43:57
44:56
41:59
39:61
41:59
36:63
54:46
33:67
28:72
97:3
93:7
55:45
65:35
d
h
h
4-FC
6
H
4
DCM
d
g
g
4-ClC
6
H
4
DCM
90:10
99:1
95:5
67:33
d
i
i
4-CF
Ph
3
C
6
H
4
DCM
71:29
d,f
j
j
DCM
81:19
d
k
k
2-NO
2-ClC
2
C
6
H
4
4
DCM
53
51
97:3
65:35
d
l
l
6
H
4
DCM
95:5
72:28
20:80
e
g
g
4-NO
2
C
6
H
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
>98
89
>98
>98
87
98:2
e
h
h
4-FC
6
H
4
80:20
44:56
e
g
g
1
1
1
1
1
4-ClC
6
H
4
73:27
47:53
e
i
i
4-CF
Ph
3
C
6
H
4
95:5
5:95
36:64
e,f
e
j
j
53:47
k
k
2-NO
2
C
6
H
4
57
91
94:6
72:28
e
l
l
2-ClC
6
H
4
41:59
35:65
a
b
c
d
e
f
Reagents and conditions: aldehyde (0.25 mmol), cyclopentanone (0.5 mmol), catalyst, solvent at 0 °C for 60 h.
Enantiomeric ratio: first eluted enantiomer:second eluted enantiomer.
1
Determined by H NMR.
All these reactions were performed in 0.5 mL of DCM.
All these reactions were performed in 2 mL of H
Reaction time: 96 h.
2
O.
g
h
i
Determined by HPLC analyses on Chiralpack AS, 254 nm, hexane/2-propanol 85:15, 1 mL/min.
Chiralpack AD, 210 nm, hexane/2-propanol 95:5, 0.5 mL/min.
Chiralpack AD, 254 nm, hexane/2-propanol 90:10, 0.5 mL/min.
Chiralcel OD-H, 210 nm, hexane/2-propanol 90:10, 0.5 mL/min.
j
k
l
Chiralcel OD-H, 254 nm, hexane/2-propanol 95:5, 1 mL/min.
Chiralpack AD, 220 nm, hexane/2-propanol 99.5:0.5, 1 mL/min.

2898
G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 18 (2007) 2894–2900
in the case of benzaldehyde and 2-chlorobenzaldehyde
entries 5, 7, 12 and 14). As far as the syn-product was
rotations were measured with a JASCO DIP-360 digital
polarimeter. Melting points were taken using a Kopfler
Reichert–Jung apparatus. IR spectra were recorded on a
Perkin–Elmer 1710 spectrophotometer.
(
concerned, the opposite enantiomer was obtained in
prevalence in water in several cases (entries 8–11). These re-
sults point to a change of asymmetric induction mechanism
depending on the solvent with some aldehyde substrates.
This particular behaviour of organocatalyst 1 is very useful
when benzaldehyde is reacted: actually, both enantiomers
of the anti-aldol product can be obtained in 90% ee simply
by changing the reaction solvent (entries 5 and 12).
4.3. Synthesis of organocatalyst
4.3.1. Methyl-3a,7a-diacetyloxy-12a-N-(L-Boc-prolinoyl)-
amino-5b-cholan-24-oate. N-Methylmorpholine (135 lL,
1.22 mmol) was added to a solution of N-Boc protected
proline (236 mg, 1.1 mmol) in anhydrous CH Cl (8 mL),
2
2
and the mixture was cooled to ꢀ20 °C, then isobutylchlo-
roformate (143 lL, 1.1 mmol) was added. The reaction
temperature was maintained at ꢀ20 °C for 5 min, then a
CH Cl solution of methyl-3a,7a-diacetyloxy-12a-amino-
3
. Conclusion
The bile acid derivative 1, bearing a D-prolinamide moiety
linked at the 12-position of cholic acid methylester, has
proven to be an efficient organocatalyst for the asymmetric
direct aldol reaction of cyclic ketones and aromatic alde-
hydes, affording aldol products in good yield and ees up
to 98%. This organocatalyst showed high versatility, giving
good results both in water and in organic solvents, where it
also works when used with 1% loading, without loss of ste-
2
2
5b-cholan-24-oate (506 mg, 1 mmol) was added dropwise
over 15 min at 0 °C. The reaction mixture was stirred for
26 h, then treated with HCl aq, NaHCO aq, NaCl aq
3
and dried over anhydrous Na SO . The organic phases
2
4
were concentrated in vacuo and the residue was purified
by flash chromatography (SiO , CH Cl /acetone 93:7).
2
2
2
2
2
Yield 250 mg, 36%. Mp 57–59 °C ½aꢁ ¼ þ28:3 (c 1.00,
D
4
f,g
1
reoselectivity, conditions that rarely afford good results.
CH Cl ). H NMR (300 MHz, CDCl ): d 0.80 (s, 3H,
2
2
3
Organocatalyst 1 also afforded the highest diastereoiso-
meric ratios reported until now in the aldol reactions of
cyclopentanone. The sense of asymmetric induction is gov-
erned by the proline moiety and, when cyclopentanone is
used as a carbonyl donor, it also depended on the solvent.
This unusual behaviour, which can be likely attributed to a
change of asymmetric induction mechanism depending on
the solvent, allows both enantiomers of an aldol product
to be obtained starting from the same chiral organocata-
lyst, simply by changing the reaction solvent.
CH ), 0.89 (d, 3H, 21-CH ), 0.93 (s, 3H, CH ), 1.00–2.60
3 3 3
0
0
(m, 28H, steroidal CH and CH , and 3 and 4 -CH of
2
2
Boc-Pro), 1.48 (s, 9H, Boc-3CH ), 1.98 (s, 3H, 3-CH CO),
3
3
0
2.10 (s, 3H, 7-CH CO), 3.47 (m, 2H, 5 -CH of Boc-Pro),
3.64 (s, 3H, CH OCO), 4.25 (br d, 1H, 2 -CH of Boc-
3
2
0
3
Pro), 4.34 (br s, 1H, 12-CH), 4.57 (m, 1H, 3-CH), 4.91
1
3
(br s, 1H, 7-CH) 6.71 (br s, NH amide). C NMR
(75 MHz, CDCl ): d 13.7, 17.4, 21.6, 21.8, 22.8, 23.4,
3
24.5, 26.3, 26.9, 27.4, 28.7, 29.5, 30.8, 31.4, 34.6, 34.8,
34.9, 38.2, 40.9, 44.6, 47.4, 48.6, 51.5, 51.6, 61.1, 71.1,
7
3.8, 80.6, 155.4, 170.3, 170.7, 170.9, 174.8. IR (KBr,
ꢀ1
cm ): 2950, 2872, 1738, 1654, 1516, 1431, 1364, 1246,
1180, 1070, 921, 852.
4. Experimental
4
.1. General procedures and materials
4.3.2.
amino-5b-cholan-24-oate. Methyl-3a,7a-diacetyloxy-12a-
N-(L-Boc-prolinoyl)amino-5b-cholan-24-oate (190 mg,
Methyl-3a,7a-dihydroxy-12a-N-(Boc-L-prolinoyl)-
TLC analyses were performed on silica gel 60 sheets; flash
chromatography separations were carried out on columns
using silica gel 60 (230–400 mesh). CH Cl and N-methyl-
0.275 mmol) was treated with MeONa solution 10% in
MeOH (1.25 mL) for 6 h at rt. The reaction was quenched
in aqueous HCl, extracted with CH Cl and dried over
2
2
morpholine were refluxed over CaH and distilled before
2
2
2
use. MeOH was refluxed over magnesium methoxide and
distilled before the use. MeONa was prepared immediately
before the use with dry MeOH and metallic Na at 0 °C.
Unless otherwise specified, the reagents were used without
any purification. Methyl-3a,7a-diacetyloxy-12a-amino-
Na SO . Organic phases were concentrated in vacuo and
2 4
the crude product was purified by column chromato-
graphy (SiO , CH Cl /acetone 6:4). Yield 66 mg, 39%.
2
2
2
2
D
2
1
Mp 95–98 °C. ½aꢁ ¼ þ15:3 (c 1.00, CH Cl ). H NMR
2
2
(300 MHz, CDCl ): d 0.78 (s, 3H, CH ), 0.87 (d, 3H,
3
3
5
b-cholan-24-oate and methyl-3a,7a-dihydroxy-12a-N-
21-CH ), 0.89 (s, 3H, CH ), 1.10–2.60 (m, 28H, steroidal
3 3
0 0
CH and CH , and 3 and 4 -CH of Boc-Pro), 1.47 (s,
2 2
(
D-prolinoyl)amino-5b-cholan-24-oate, 1, were obtained
0
9H, Boc-3CH ), 3.40 (m, 2H, 5 -CH of Pro), 3.49 (m,
3 2
as previously described and matched the reported
characteristics.
7
1H, 3-CH) 3.64 (s, 3H, CH OCO), 3.84 (br s, 1H, 12-
3
1
3
CH), 4.27 (br s, 1H, 7-CH), 7.15 (br s, NH amide).
C
4
.2. Instrumentation
NMR (75 MHz, CDCl ): d 13.5, 17.4, 22.6, 23.4, 24.3,
3
2
6.0 27.5, 28.6, 29.4, 30.8, 30.9, 31.3, 34.7, 34.8, 35.1,
1
13
H and C NMR spectra were recorded in CDCl on a
35.3, 39.6, 40.1, 41.5, 44.1, 44.4, 47.3, 48.7, 51.5, 51.9,
60.6, 68.2, 71.9, 80.8, 155.7, 171.2, 174.7.
3
Varian Gemini-300 300 MHz NMR spectrometer, using
TMS as the external standard. The following abbreviations
are used: s = singlet, d = doublet, dd = double doublet,
t = triplet, m = multiplet, br = broad. HPLC analyses
were performed on a JASCO PU-980 intelligent HPLC
pump equipped with JASCO UV-975 detector. Optical
4.3.3. Methyl-3a,7a-dihydroxyl-12a-(L-prolinoyl)amino-5b-
cholan-24-oate. A solution of methyl-3a,7a-dihydroxy-
12a-N-(Boc-L-prolinoyl)amino-5b-cholan-24-oate (66 mg,
0.275 mmol) in CH Cl (5 mL) was treated with a large
2
2

G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 18 (2007) 2894–2900
2899
excess of TFA (2 mL) and stirred at rt for 15 min. The reac-
Acknowledgements
tion mixture was washed with 5% NaHCO to remove the
3
excess of acid and extracted with CH Cl (3 ꢂ 30 mL). The
The work was supported by the University of Pisa, MIUR
(Project ‘High performance separation systems based on
chemo- and stereoselective molecular recognition’ Grant
2005037725). Mrs. Monica Morelli is gratefully acknow-
ledged for helping with the synthesis of L-prolinamide
derived organocatalyst.
2
2
organic phase was washed with brine (3 ꢂ 50 mL) then
dried over anhydrous Na SO . Organic phases were con-
2
4
centrated in vacuo and the crude product was purified by
column chromatography (SiO , AcOEt/MeOH 7:3).Yield
2
22
2
5 mg, 38%. Mp 103–105 °C. ½aꢁ ¼ þ28:3 (c 1.00,
D
1
CH Cl ). H NMR (300 MHz, CDCl ): d 0.79 (s, 3H,
2
2
3
CH ), 0.83 (d, 3H, 21-CH ), 0.88 (s, 3H, CH ), 0.90–2.70
3
3
3
0
0
(
m, 28H, steroidal CH and CH , and 3 and 4 -CH of
Pro), 3.12 (m, 2H, 5 -CH of Pro), 3.45 (m, 1H, 3-CH),
References
2
2
0
2
3
.65 (s, 3H, CH OCO), 3.87 (br s, 1H, 12-CH), 4.00 (br
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3
0
2
000, 122, 2395–2396.
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1
3
3
4
2
3
6
2
1
3.4, 25.6, 26.6, 27.6, 30.8, 31.1, 31.4, 34.8, 34.9, 35.0,
5.2, 39.3, 39.6, 41.5, 43.8, 44.6, 47.2, 48.7, 51.5, 52.1,
0.6, 68.2, 70.3, 71.9, 171.8, 174.6. IR (KBr, cm ): 2944,
864, 1734, 1714, 1658, 1648, 1623, 1573, 1543, 1508,
437, 1382, 1261, 1166, 1075, 985.
(
ꢀ
1
2
Angew. Chem., Int. Ed. 2006, 45, 7506–7525; (g) Desimoni,
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651; (h) Aldriga, S. Chem. World 2006, 3, 58–61; (i) Wu, G.;
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.4. General procedure for aldol reaction
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(
0.25 mmol) was added and the mixture was stirred at the
indicated temperature for the indicated time. This solution
3. Ley, S. Asymm. Synth. 2007, 201–206.
was quenched in aqueous NH Cl (1 mL) and extracted
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4
with AcOEt (1 mL), then dried over anhydrous Na SO
2
4
1
8, 1155–1158; (c) Wang, C.; Jiung, Y.; Zhang, X.-X.; Huang,
Y.; Li, B.-G.; Zhang, G. L. Tetrahedron Lett. 2007, 48, 4281–
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and concentrated under reduced pressure. The residue
was purified over a small column of silica gel (AcOEt/hex-
ane 1:1) and after concentration analysed with HPLC and
4
1
Catal. 2007, 349, 812–816; (e) Amedjkouh, M. Tetrahedron:
Asymmetry 2007, 18, 390–399; (f) Maja, V.; Raj, M.; Singh,
V. K. Org. Lett. 2007, 9, 2593–2595; (g) Russo, A.; Botta, G.;
Lattanzi, A. Synlett 2007, 755–799.
H NMR. All the known aldol adducts matched the
4
–6
reported characteristics.
4
.4.1.
2-(Hydroxy-(p-fluoro)methyl)cyclopentan-1-one.
5. (a) Zhang, L.; Gao, Q.; Gao, J.; Xiao, J.; Li, C. J. Catal.
1
2
007, 250, 360–364; (b) Guillena, G.; Hita, M.; Najera, C.
syn-Diastereoisomer H NMR (200 MHz, CDCl ) d:
1
J = 11.4 Hz, J = 4.4 Hz 1H, CHCHOH), 4.63 (s, 1H,
CHCHOH), 5.29 (d, 1H, J = 2.8 Hz, CHCHOH) 7.04 (t,
J = 7.8 Hz, 2H, aromatic), 7.30 (dd, J = 6.0 Hz, J =
3
Tetrahedron: Asymmetry 2007, 18, 1272–1277; (c) Gryko, D.;
Saletra, W. J. Org. Biomol. Chem. 2007, 5, 2148–2153; (d)
Zhang, L.; Liu, S.; Xu, H.; Chey, J.-P. Tetrahedron 2007, 63,
.28–2.52 (m, 6H, CH2 cyclopentanone), 2.71 (dd,
1
2
1
923–1930; (e) Chen, X.-H.; Luo, S.-W.; Tang, Z.; Cun,
1
2
L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Chem. Eur. J.
2007, 13, 689–701; (f) Giacalone, F.; Guttadamia, M.;
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5527–5529; (h) Chimni, S. S.; Mahajan, D. Tetrahedron:
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Pericas, M. A. Org. Lett. 2006, 8, 4653–4655; (j) Guillena, G.;
Hita, M.; Najera, C. Tetrahedron: Asymmetry 2006, 17, 1493–
2
6
.6 Hz, 2H, aromatic). Anal. Calcd for C H FO : C,
9.22; H, 6.29; F, 9.12; O, 15.37. Found:, 69.32; H, 6.44;
12 13 2
F, 9.07; O, 15.50. Enantiomeric excess was determined by
HPLC with a Chiralpak AD column (95:5 hexane/2-propa-
nol), rt, 220 nm, 0.5 mL/min; syn-diastereoisomer: t =
2
3
R
2.55 min, tR = 27.47 min;
1.69 min, t = 35.72 min.
anti-diastereomer: t =
R
R
1
497; (k) Ibrahem, I.; Zan, W.; Xu, Y.; Cordova, A. Adv.
4
.4.2.
2-(Hydroxy-(p-chloro)methyl)cyclopentan-1-one.
Synth. Catal. 2006, 348, 211–222; (l) Mase, N.; Najak, Y.;
Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F.,
III J. Am. Chem. Soc. 2006, 128, 734–735.
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L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S. Tetrahedron:
Asymmetry 2006, 17, 3351–3357; (c) Luo, S.; Mi, X.; Zhang,
L.; Liu, S.; Xu, H.; Cheng, J.-P. Tetrahedron 2007, 63, 1923–
1
syn-Diastereoisomer H NMR (200 MHz, CDCl ) d:
1
1
3
.22–2.38 (m, 6H, CH2 cyclopentanone), 2.90 (t, J =
3.2 Hz 1H, CHCHOH), 4.63 (s, 1H, CHCHOH), 5.23
6
(
br s, 1H, CHCHOH) 7.32 (dd, J = 22.8 Hz, J = 8.4
1 2
4
5
1
H, aromatic). Anal. Calcd for C H ClO : C, 64.15; H,
.83; Cl, 15.78; O, 14.24. Found:, 64.12; H, 5.88; Cl,
5.90; O, 14.30. Enantiomeric excess was determined by
12 13 2
1
930; (d) Cordova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.;
HPLC with a Chiralpak AS column (90:10 hexane/2-pro-
panol), rt, 220 nm, 1 mL/min; syn-diastereoisomer: t =
1
1
Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383–5397; (e)
Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006,
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A. Org. Biomol. Chem. 2005, 4, 38–40; (g) Wu, Y.-S.; Chen,
R
2.35 min, tR = 14.65 min; anti-diastereoisomer: tr =
6.85 min, t = 21.11 min.
R

2900
G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 18 (2007) 2894–2900
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7
8
9
. Puleo, G. L.; Masi, M.; Iuliano, A. Tetrahedron: Asymmetry
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2
3
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