L-proline diamides with an axially chiral binaphthylene backbone as efficient organocatalysts for direct asymmetric aldol reactions: The effect of acetic acid

Article abstract of DOI:10.1055/s-2006-958924

A series of L-proline diamides derived from optically active 1,1′-binaphthyl-2,2′-diamines have been synthesized in good yields and their catalytic abilities as organocatalysts in direct asymmetric aldol reactions have been evaluated. Among these organo-c

Full text of DOI:10.1055/s-2006-958924

PAPER
197
L-Proline Diamides with an Axially Chiral Binaphthylene Backbone as
Efficient Organocatalysts for Direct Asymmetric Aldol Reactions:
The Effect of Acetic Acid
B
G
inaphthylene Ba
c
u
kbone
L
-Pro
a
line
D
iamid
n
es as Organo
g
catalysts for
-
A
symm
N
etric Aldol Reacti
i
ons ng Ma, Yun-Peng Zhang, Min Shi*
School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 MeiLong Road, Shanghai 200237,
P. R. of China
Fax +86(21)64166128; E-mail: Mshi@mail.sioc.ac.cn
Received 11 August 2006; revised 2 October 2006
bonding by proline and its derivatives. Thus far, it has
Abstract: A series of L-proline diamides derived from optically ac-
been realized that a subtle change in the backbone of the
catalyst may affect the strength of hydrogen bonding,
tive 1,1¢-binaphthyl-2,2¢-diamines have been synthesized in good
yields and their catalytic abilities as organocatalysts in direct asym-
metric aldol reactions have been evaluated. Among these organo- such that a dramatic enhancement of activity and selectiv-
catalysts, bis(prolinamides) exhibit higher catalytic abilities. The ity may be anticipated. Recently, various organocatalysts
aldol reaction of arylaldehydes with acetone or cyclohexanone pro-
derived from L-proline and diamines have exhibited very
ceeds smoothly using the organocatalyst (10 mol%) in the presence
high catalytic activity and stereoselectivity in direct aldol
of acetic acid (10 mol%) as an additive in toluene at –40 °C for 48–
reactions. For example, Zhao and co-workers synthesized
7
2 hours to give the corresponding aldol products in high yields
several C -symmetric bisamide organocatalysts from L-
2
(
<90%) and with good to high enantioselectivities (<98%) and high
proline and 1,2-diphenylethylenediamine. They found
that the enantioselectivities achieved in the aldol reaction
anti-diastereoselectivities (<98:2).
Key words: 1,1¢-binaphthyl-2,2¢-diamine, organocatalysts, direct
asymmetric aldol reactions, L-proline diamides, acetic acid
catalyzed by C -symmetric bis(prolinamides) were
2
strongly influenced by the chiral backbone of the cata-
lysts. Using (1S,2S)-1,2-diphenylethylenediamine as a
chiral backbone, <98% ee can be achieved with small
Asymmetric organocatalysis has recently attracted much
attention in asymmetric catalysis. This has resulted in a
new field of research and the exploration of the funda-
mental chemical parameters of asymmetric organocataly-
sis, such as reactivity, selectivity, and mechanism, has
lead to the discovery of many novel reactions and cata-
8
loading of the catalyst (10 mol%). Xiao and co-workers
revealed that unsymmetric bisamides derived from
(
1R,2R)-cyclohexane-1,2-diamine and L-proline are ef-
fective catalysts for the aldol reaction of cyclohexanone
with arylaldehydes affording the corresponding aldol
products in good yields and with <97% ee and diastereo-
1
lysts. In this endeavor, the design and synthesis of multi-
9
selectivity anti/syn <99:1. Furthermore, Gryko and co-
functional chiral organocatalysts is of great importance.
The ability of simple, small organic compounds from
readily available homochiral compounds to act as cata-
lysts, as if an enzyme, represents a remarkable synthetic
alternative to many established asymmetric reactions.
Among the various enantiomerically pure small organic
molecules available, amino acids and peptides, as well as
cinchona alkaloids, are extremely interesting asymmetric
organocatalysts, with useful levels of enantioselectivity
for a wide range of transformations.2
workers recently synthesized bis(prolinamides) derived
from L-proline and racemic 1,1¢-binaphthyl-2,2¢-diamine
and used them as organocatalysts in the direct asymmetric
aldol reaction of acetone with 4-nitrobenzaldehyde to give
the corresponding aldol reaction product in moderate
yield (<79%) and enantioselectivity (<88%). In addition,
moderate diastereoselectivity (anti/syn <70:30) and low
enantioselectivity (<17~45% ee) have been attained in the
aldol reaction of cyclopentanone or cyclohexanone with
4
-nitrobenzaldehyde after prolonged reaction times (68 h)
1
0
The aldol reaction is the most important carbon–carbon
at 4 °C.
3
bond-forming reactions in organic synthesis. Several ef-
Thus far, we have been working on the design and synthe-
sis of chiral ligands based on axially chiral 1,1¢-binaph-
thyl-2,2¢-diamine and we have been examining their ability
to induce chirality in asymmetric catalysis.11 Hence, we
attempted to synthesize chiral L-proline diamide organo-
catalysts derived from optically active 1,1¢-binaphthyl-
ficient asymmetric methodologies for this reaction using
organocatalysts have been developed, of which the most
remarkable advances in the domain of L-proline and its
derivative catalysts have been made by List and Barbas et
4
5
al. On the other hand, the groups of MacMillan, Jørgens-
6
7
en, and Yamamoto are also pioneering workers in this
field. These catalysts are believed to catalyze aldol reac-
tions by stabilizing the transition state through hydrogen
2
,2¢-diamine so that we could assess their efficacy in di-
rect asymmetric aldol reactions. We found that the aldol
reaction of arylaldehydes with acetone or cyclohexanone
proceeds smoothly using a chiral bis(prolinamide) cata-
lyst (10 mol%) in the presence of acetic acid (10 mol%) as
an additive in toluene at –40 °C for 48–72 hours to give
SYNTHESIS 2007, No. 2, pp 0197–0208
x
x
.
x
x
.2
0
0
7
Advanced online publication: 12.12.2006
DOI: 10.1055/s-2006-958924; Art ID: F12606SS
Georg Thieme Verlag Stuttgart · New York
©

1
98
G.-N. Ma et al.
PAPER
the corresponding aldol products in high yields (<90%), (R)-3a (Schemes 2 and 3). Removal of the tert-butoxycar-
and good to high enantioselectivities (<98%) as well as bonyl protecting group by treatment with excess trifluoro-
high anti-diastereoselectivities (<98:2). Herein, we report acetic acid produced the desired monoprolinamides (S)-
the details.
and (R)-4b and (S)- and (R)-4c in good yields (Schemes 2
and 3).
Since optically active (S)- and (R)-1,1¢-binaphthyl-2,2¢-
diamines (S)- and (R)-2 have been widely used in transi- The catalytic abilities of these organocatalysts 4a–c
tion-metal-catalyzed asymmetric reactions, we believed (Figure 1) were evaluated in the direct asymmetric aldol
that if an optically active diamine (S)- or (R)-2 was used reaction of 4-nitrobenzaldehyde (7a) with acetone at room
as the backbone of a bis(prolinamide), the efficiency of temperature (25 °C). The results are summarized in
the corresponding organocatalysts in direct asymmetric Table 1. The organocatalyst (S)-4a (10 mol%), derived
1
2
aldol reactions could be improved. Thus, we attempted from L-proline with (S)-1,1¢-binaphthyl-2,2¢-diamine,
to synthesize some chiral monoprolinamides and bis(pro- produced the corresponding aldol reaction product (R)-8a
linamides) directly from optically active diamines (S)- or with higher enantiomeric excess than its diastereomer
(
1
R)-2. An optically active diamine (S)-2 or (R)-2 (284 mg, (R)-4a (10 mol%) in the presence of acetic acid (10 mol%)
.0 mmol), prepared according to the literature, was cou- under identical conditions (Table 1, entries 1 and 2). In
1
3
pled with 1-(tert-butoxycarbonyl)-L-proline (1, 454 mg, general, under identical conditions monoprolinamides
2
.2 mmol) in the presence of N,N¢-dicyclohexylcarbodi- (S)-4b, (R)-4b, (S)-4c, and (R)-4c were not as effective as
imide (474 mg, 2.20 mmol) and 4-(dimethylamino)pyri- the bis(prolinamides) (S)-4a and (R)-4a (Table 1, entries
dine (20 mg, 0.16 mmol), affording the corresponding N- 3–6). Using a combination of (S)-4a and (R)-4a as the or-
9
(
(
tert-butoxycarbonyl)-protected bis(prolinamide) (S)-3 or ganocatalyst in the same reaction produced the aldol reac-
R)-3 in good yield. Next, these compounds were treated tion product (R)-8a in 60% ee under the standard
with excess trifluoroacetic acid to remove the tert-bu- conditions (Table 1, entry 7).
toxycarbonyl protecting group, leading to the formation of
the corresponding pure bis(prolinamide) (S)-4a or (R)-4a
in good yield (Scheme 1).
In order to improve the yield and enantioselectivity of 8a,
the effects of temperature, solvent, and additive on the al-
dol reaction were investigated using (S)-4a as the organo-
N-tert-Butoxycarbonyl-protected monoprolinamides (S)- catalyst. The results are given in Table 2. It was found that
b and (R)-3b bearing an N-acetyl group and N-tert-bu- the enantioselectivity was highly dependent on the tem-
toxycarbonyl-protected monoprolinamides (S)-3c and perature and the solvent employed. The enantiomeric ex-
R)-3c bearing an N-tosyl group were prepared from the cess value of 8a increased to 84% when the reaction
3
(
corresponding optically active N-monoacetylated di- temperature was lowered to –40 °C in neat acetone
amines (S)- and (R)-5 and N-monotosylated diamines (S)- (Table 2, entries 2–5). We also found that acetic acid as an
and (R)-6 in the same manner as that described for (S)- and additive has a remarkable effect on the catalytic ability of
O
N
NH2
NH2
NH
NH
Boc
N
O
(S)-2
(S)-3a
Boc
O
DCC, DMAP
r.t., 12 h
or
+
or
N
OH
Boc
O
NH2
NH2
1
N
NH
Boc
NH
O
N
(R)-2
Boc
(R)-3a
O
O
N
H
N
NH
NH
H
TFA–CH2Cl2 (1:4)
r.t., 2 h
or
NH
O
NH
O
N
N
H
H
(S)-4a
(R)-4a
Scheme 1 Synthesis of bis(prolinamides) (S)-4a and (R)-4a.
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

PAPER
Binaphthylene Backbone L-Proline Diamides as Organocatalysts for Asymmetric Aldol Reactions
199
NHAc
NH2
NHTs
NH2
O
O
N
OH
O
S
N
OH
Boc
Cl
Me
Boc
(
S)-5
(S)-6
Ac2O, AcOH
r.t., 12 h
1
O
1
(
S)-2 or (R)-2
or
(S)-2 or (R)-2
or
DCC, DMAP,
r.t., 12 h
r.t., 12 h
DCC, DMAP,
r.t., 12 h
NHAc
NH2
NHTs
NH2
(
R)-5
(R)-6
NHAc
NH
NHTs
NHAc
NH
NHTs
NH
NH
O
N
H
N
O
O
H
N
N
O
Boc
(S)-4b
Boc
(S)-4c
(S)-3b
(S)-3c
TFA/CH2Cl2 (1:4)
r.t., 2 h
TFA/CH2Cl2 (1:4)
r.t., 2 h
or
or
or
or
NHAc
NH
NHTs
NH
NHAc
NH
NHTs
NH
N
N
O
N
H
O
N
O
O
H
Boc
Boc
(
R)-3b
(R)-3c
(R)-4b
(R)-4c
Scheme 2 Synthesis of monoprolinamides (S)-4b and (R)-4b.
Scheme 3 Synthesis of monoprolinamides (S)-4c and (R)-4c.
(
S)-4a, since reaction proceeded slowly at 0 °C when it dol product (R)-8a in good yields and with 34–86% ee
was performed without the addition of acetic acid (Table 2, entries 6–9). In toluene, (R)-8a was obtained in
Table 2, entries 1 and 3). Increasing the amount of acetic 82% yield and with 93% ee in the presence of acetic acid
(
acid to 40 mol% did not significantly affect the reaction (10 mol%) and 50% yield and with 92% ee in the presence
rate (Table 2, entries 2 and 3). The solvent employed sig- of acetic acid (5 mol%) (Table 2, entries 10 and 12), but
nificantly affected the enantiomeric excess of (R)-8a at in the absence of acetic acid (R)-8a was still obtained in
–
40 °C. We found the use of 1,2-dichloroethane, chloro- 75% yield and with 90% ee thus the isolated yield and the
form, N,N-dimethylformamide, and dichloromethane as enantiomeric excess value decreased slightly under iden-
the solvent under identical conditions gave the desire al- tical conditions in the absence of acetic acid (Table 2, en-
O
O
NHAc
N
H
NH
NH
N
NH
NH
H
NH
O
N
N
H
H
N
O
O
H
(
S)-4a
(R)-4a
(S)-4b
NHAc
NHTs
NHTs
NH
NH
O
NH
O
N
N
N
O
H
H
H
(
R)-4b
(S)-4c
(R)-4c
Figure 1 C -Symmetric bis(prolinamide) catalysts 4a and C -symmetric monoprolinamide catalysts 4b,c.
2
1
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

2
00
G.-N. Ma et al.
PAPER
Table 1 Direct Asymmetric Aldol Reaction of Acetone and 4-Nitrobenzaldehyde (7a) Using Various L-Proline Amide Organocatalysts 4a–ca
O
OH
O
O
catalyst (S)- and (R)-4a–c (10 mol%)
+
AcOH (10 mol%), r.t
O2N
2
O N
7a
(R)-8a
b
c
Configd
Entry
Catalyst
(S)-4a
(R)-4a
(S)-4b
(R)-4b
(S)-4c
(R)-4c
Temp (°C)
Time (h)
12
Yield (%)
ee (%)
1
2
3
4
5
6
25
25
25
25
25
25
25
89
90
78
68
75
77
80
60
50
54
44
54
54
60
R
R
R
R
R
R
R
12
24
24
24
24
7
(S)-4a + (R)-4a
18
a
Conditions: 7a (75.6 mg, 0.5 mmol), acetone (2.0 mL), catalyst (10 mol%), AcOH (10 mol%), 8–24 h.
Isolated yields.
Determined by chiral HPLC analysis using a Chiralpak AS-H column.
b
c
d
The absolute configuration was determined by comparing the sign of the specific rotation with an authentic sample.
tries 10 and 11). We also examined various organic acids nesulfonic acid, benzoic acid, or formic acid, (R)-8a was
as additives in this reaction. We found that 8a was formed obtained in moderate yields and 68–91% ee (Table 2, en-
in trace amounts in the presence of trifluoroacetic acid or tries 15–17). Therefore, the optimized reaction conditions
trifluoromethanesulfonic acid under identical conditions use (S)-4a (10 mol%) as the organocatalyst in toluene
(
Table 2, entries 13 and 14). With the addition of 4-tolue- with the addition of 10 mol% of acetic acid at –40 °C.
Table 2 Direct Asymmetric Aldol Reaction of Acetone and 4-Nitrobenzaldehyde (7a) Using L-Prolinamide Organocatalyst (S)-4a under
Various Conditionsa
O
OH
O
O
H
(S)-4a (10 mol%)
+
O2N
2
O N
7a
(R)-8a
b
c
Entry
Additive
–
Solvent
–d
Temp (°C)
0
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
72
48
48
72
72
48
72
72
72
72
72
72
58
90
88
85
79
96
77
67
67
82
75
50
65
61
60
77
84
34
65
74
86
93
90
92
AcOH (40 mol%)
AcOH (10 mol%)
AcOH (10 mol%)
AcOH (10 mol%)
AcOH (10 mol%)
AcOH (10 mol%)
AcOH (10 mol%)
AcOH (10 mol%)
AcOH (10 mol%)
–
–d
0
–d
0
–d
–20
–40
–40
–40
–40
–40
–40
–40
–40
–d
DCE
CHCl3
DMF
CH Cl
2
2
1
1
1
0
1
2
toluene
toluene
toluene
AcOH (5 mol%)
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

PAPER
Binaphthylene Backbone L-Proline Diamides as Organocatalysts for Asymmetric Aldol Reactions
201
Table 2 Direct Asymmetric Aldol Reaction of Acetone and 4-Nitrobenzaldehyde (7a) Using L-Prolinamide Organocatalyst (S)-4a under
a
Various Conditions (continued)
O
OH
O
O
H
(S)-4a (10 mol%)
+
O2N
2
O N
7a
(R)-8a
b
c
Entry
Additive
Solvent
toluene
toluene
toluene
toluene
toluene
Temp (°C)
–40
Time (h)
Yield (%)
ee (%)
1
1
1
1
1
3
4
5
6
7
TFA (10 mol%)
TfOH (10 mol%)
TsOH (10 mol%)
96
96
96
96
96
trace
trace
25
n.d.e
n.d.e
68
–40
–40
PhCO H (10 mol%)
–40
58
90
2
HCO H (10 mol%)
–40
50
91
2
a
b
c
d
e
Conditions: 7a (75.6 mg, 0.5 mmol), acetone (0.5 mL), (S)-4a (10 mol%), 48–96 h.
Isolated yields.
Determined by chiral HPLC using a Chiralpak AS-H column.
Acetone was the solvent.
Not determined.
To test the substrate generality of this interesting organo- 4a and 5 mol% of acetic acid, the reaction also proceeded
catalyst, the aldol reaction of various aldehydes with ace- smoothly to give the corresponding aldol product (R)-8a
tone was examined under these optimized conditions. The in 55% yield and with 92% ee, which is comparable to
results are summarized in Table 3. As shown, we found those results obtained using of 10 mol% of (S)-4a and 10
that arylaldehydes with a strongly electron-withdrawing mol% of acetic acid under identical conditions (Table 3,
group, such as a nitro group, on the benzene ring gave the entries 1 and 2).
corresponding aldol products (R)-8a–c in good yields
Moreover, we also examined the direct aldol reaction of
with 92–98% ee (Table 3, entries 1, 3, and 4). For arylal-
cyclohexanone and cyclopentanone with arylaldehydes
dehydes bearing a halogen atom on the benzene ring the
under these optimized reaction conditions. The results us-
corresponding aldol products were produced in moderate
ing cyclohexanone as a substrate are summarized in
yields and with 67–92% ee (Table 3, entries 5–8). Fur-
Table 4. For various arylaldehydes bearing an electron-
thermore, it is noteworthy that even using 5 mol% of (S)-
Table 3 Scope of Arylaldehydes 7 for the Direct Aldol Reaction with Acetone under Optimal Conditionsa
OH
O
O
O
(S)-4a (10 mol%), AcOH (10 mol%)
+
R
R
H
toluene, –40 °C, 48–72 h
(R)-8
7
b
c
Configd
Entry
R
Product
8a
Yield (%)
ee (%)
1
2
3
4
5
6
7
4-O NC H
83
55e
86
86
67
91
60
57
93
R
R
R
R
R
R
R
R
2
6
4
4
4
4
4-O NC H
8a
92
2
6
3-O NC H
8b
95
2
6
2-O NC H
8c
98
2
6
4-ClC H
8d
81
6
4
4
2-ClC H
8e
92
6
4-BrC H
8f
76
6
4
8
4-FC H
8g
67
6
4
a
Conditions: 7a–g (0.5 mmol), acetone (0.5 mL), (S)-4a (10 mol%), AcOH (10 mol%), toluene (3.0 mL), –40 °C, 48–72 h.
Isolated yields.
Determined by chiral HPLC using a Chiralpak AS-H or AD-H or a Chiralcel OD-H or OJ-H column.
The absolute configuration was determined by comparing the sign of the specific rotation with an authentic sample.
In the presence of (S)-4a (5 mol%) and AcOH (5 mol%).
b
c
d
e
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02
G.-N. Ma et al.
PAPER
Table 4 Scope of Aldehyde 7 for the Direct Aldol Reaction with Cyclohexanone under Optimal Conditionsa
OH
O
O
O
(S)-4a (10 mol%),
AcOH (10 mol%)
OH
O
R
+
R
H
R
+
toluene, –40 °C, 48–72 h
7
anti-9
syn-9
b
c
d
Entry
R
Product
9a
Yield (%)
dr (anti/syn)
ee (%) anti
1
2
3
4
5
6
4-O NC H
90
83
83
71
70
61
45
98:2
95
95
90
98
96
92
80
2
6
4
4
4
3-O NC H
9b
98:2
2
6
2-O NC H
9c
98:2
2
6
4-ClC H
9d
97:3
6
4
4-BrC H
9e
95:5
6
4
4-FC H
9f
92:8
6
4
7
C H
9g
97:3
6
5
a
Conditions: 7a–g (0.5 mmol), cyclohexanone (0.5 mL), (S)-4a (10 mol%), AcOH (10 mol%), toluene (3.0 mL), –40 °C, 48–72 h.
b
c
d
Isolated yields.
1
Determined by analysis of anti/syn mixtures by H NMR and chiral HPLC.
Determined by chiral HPLC using a Chiralpak AS-H or AD-H or a Chiralcel OD-H, or OJ-H column.
withdrawing group, such as a nitro group or a halogen at- formation of the enamine intermediate, but excessive ace-
om, on the benzene ring the reaction with cyclohexanone tic acid may have a negative effect on the hydrogen bond-
proceeded smoothly to furnish the corresponding aldol ing of the diamide, which in turn depresses the catalytic
adducts 9a–f with excellent anti-diastereoselectivity efficacy.9
(
(
<92:8–98:2) and high enantioselectivity (<90–98% ee)
Table 4, entries 1–6). Only in the case of the aldol reac-
In conclusion, we have synthesized a series of L-prolin-
amide organocatalysts bearing an axially chiral binaph-
thylene backbone and their catalytic activity has been
examined using direct asymmetric aldol reactions. We
found that bis(prolinamide) organocatalysts are superior
to monoprolinamide organocatalysts in reactivity and ste-
reoselectivity. Under these optimized reaction conditions,
tion of cyclohexanone with benzaldehyde was the corre-
sponding aldol product 9g obtained with lower
enantiomeric excess (80% ee), although with excellent
anti-diastereoselectivity, presumably due to its electron-
rich character (Table 4, entry 7).
The reaction of 4-nitrobenzaldehyde (7a) with cyclopen- good to excellent enantioselectivities (<98% ee) can be
tanone was also investigated to examine the scope of the achieved in the aldol reaction of arylaldehydes with ace-
aldol donors. The corresponding aldol product 10 was tone in good yields in the presence of acetic acid in tolu-
produced in 84% yield with an anti/syn ratio of 30:70 and ene at –40 °C. On the other hand, good to high
with 98% ee for the anti-diastereomer and with 81% ee for enantioselectivities (<98%) as well as high anti-diaste-
the syn-diastereomer (Scheme 4). Comparing the result reoselectivities (<98:2) can be realized in the aldol reac-
for cyclopentanone with that of cyclohexanone, it is inter- tion of cyclohexanone with arylaldehydes in toluene at
esting to note that organocatalyst (S)-4a has the opposite –40 °C. Further work on determining the reaction mecha-
performance for these two substrates in terms of diaste-
OH
reoselectivity.
O
O
O
(S)-4a (10 mol% ),
The mechanism of the diamide–Brønsted acid catalyzed
aldol addition is the subject of an extensive ongoing in-
AcOH (10 mol%)
H
+
toluene, –40 °C, 48 h
O2N
O2N
1
4–16
vestigation, but it remains unsolved.
For the purpose
yield: 84%,
anti/syn 30:70
anti-10
7
a
of the detailed discussion, we give a proposed mechanism
as shown in Scheme 5 based on a prolinamide-catalyzed
process through a six-membered, chairlike transition
state, which is derived from a generally accepted iminium
ion and enamine intermediate found in proline-catalyzed
direct asymmetric aldol reactions, locating the re-face of
the acceptor proximate to the attack by the enamine to
give the corresponding aldol product with R-configura-
tion. Acetic acid as an additive is also indispensable in this
catalysis process, as it provides a proton to accelerate the
98% ee
OH
O
+
O2N
syn-10
8
1% ee
Scheme 4 Reaction of 4-nitrobenzaldehyde (7a) with cyclopent-
anone.
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

PAPER
Binaphthylene Backbone L-Proline Diamides as Organocatalysts for Asymmetric Aldol Reactions
203
AcOH
AcO
iminium ion
AcO
O
O
O
O
N
N
H
N
NH
N
N
H
– H2O
H
H
H
AcOH
catalyst
O
regeneration
N
N
AcO
H
O
O
OH
N
enamine
intermediate
H
N
H
R
OH
aldol product
RCHO
HO
R
+
H2O
AcOH
re-facial attack
O
N
N
H
O
N
N
AcO
OH
R
O
R
AcO
H
six-membered transition state
Scheme 5 Plausible enamine mechanism of the direct asymmetric aldol reaction catalyzed by bis(prolinamide) (S)-4a.
nism and exploration of direct asymmetric Michael addi- the soln was cooled to 0 °C and stirred for 30 min. A soln of (S)- or
(
R)-1,1¢-binaphthyl-2,2¢-diamine [(S)-2 or (R)-2] (284 mg, 1.0
tions using these L-prolinamide organocatalysts are
currently underway.
mmol) in CH Cl (10 mL) was added dropwise over 15 min. When
the addition was complete, the mixture was warmed to r.t. and
stirred for a further 12 h. Dicyclohexylurea was filtered off and the
2
2
Unless otherwise stated, materials were purchased from commer-
cial suppliers and used without further purification. CH Cl and 1,2-
solvent was removed under reduced pressure. Then, H O (5 mL)
was added and the product was extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed consecutively with 1.0
2
2
2
dichloroethane were freshly distilled from CaH ; THF and toluene
2
were distilled from Na under argon; hexane, petroleum ether, and
EtOAc for flash column chromatography and recrystallization were
distilled before use. Melting points were determined on a digital
melting point apparatus and temperatures were uncorrected. Optical
rotations were determined at 589 nm (sodium D line) by using a Per-
M KHSO
mL), and H
4
(1 × 25 mL), H
2
2
O (1 × 25 mL), 10% aq NaHCO
3
(1 × 25
O (1 × 25 mL) and dried (anhyd Na
SO ). The solvent
2
4
was evaporated to provide (S)-3a and (R)-3a, which were used in
the next reaction without further purification. The corresponding
pure compounds (S)-3a and (R)-3a were obtained by recrystalliza-
kin-Elmer 341 MC digital polarimeter; [a] values are given in
tion (CH Cl , hexane).
2 2
D
–
1
2
–1 1
units of 10 deg ·cm ·g . H NMR spectra were recorded on a Bruk-
er AM-300 (300 MHz). Chemical shifts are reported from the sol-
Bis[1-(tert-butoxycarbonyl)prolinamide] (S)-3a
White solid; yield: 610 mg (91%); mp 238–240 °C.
1
3
vent resonance as the internal standard (CDCl : d = 7.26). C NMR
3
spectra were recorded on a Bruker AM-300 (75 MHz) with com-
20
[
a]D –199.4 (c 1.025, CHCl3).
plete proton decoupling (CDCl : d = 77.0). IR spectra were recorded
3
–
1
IR (film): 3320, 2925, 2848, 1622, 1435 1087, 1039, 641 cm .
on a Bio-Rad FTS-185. Flash column chromatography was per-
formed using silica gel (300–400 mesh). For TLC, silica gel plates
1
H NMR (300 MHz, CDCl ): d = 0.80–1.15 (m, 4 H, CH ), 1.30 [s,
3
2
(
Huanghai GF254) were used and compounds were visualized by ir-
18 H, C(CH ) ], 1.50–1.95 (series of m, 6 H, CH ), 2.60–2.80 (m, 2
3
3
2
radiation with UV light and/or by treatment with phosphomolybdic
acid in EtOH soln followed by heating. Chiral HPLC was per-
formed on a Shimadzu SPD-10A series with chiral columns [Chiral-
pak AS-H or AD-H or Chiralcel OD-H or OJ-H columns 4.6 × 250
mm (Daicel Chemical Ind., Ltd.)]. Elementary analysis (CHN) was
taken on a Carlo-Erba 1106 analyzer. MS spectra were recorded by
EI and HRMS was measured on a HP-5989 instrument. All aldol re-
actions were carried out under an atmosphere of air in a closed sys-
tem. Racemic aldol products were synthesized by treatment of the
corresponding substrates with aq NaOH (1% w/v) at 0 °C.
H, CH ), 4.05–4.10 (m, 2 H, CH), 7.11–7.20 (m, 2 H, ArH), 7.24–
7.36 (m, 2 H, ArH), 7.38–7.48 (m, 2 H, ArH), 7.88–8.00 (m, 4 H,
ArH), 8.06–8.15 (m, 2 H, ArH), 8.82 (br s, 2 H, NHCO).
2
+
MS (EI): m/z (%) = 678.5 (3.67) [M ], 408.2 (9.29), 267.2 (10.52),
7
0.1 (100).
Bis[1-(tert-butoxycarbonyl)prolinamide] (R)-3a
White solid; Yield: 600 mg (88%); mp 221–223 °C.
[
a
]
2
0
–
2
6
.
4
(
c
1
.
0
4
5
,
C
H
C
l
)
.
D
3
–
1
IR (film): 3320, 2925, 2848, 1622, 1435, 1087, 1039, 641 cm .
N,N¢-1,1¢-Binaphthalene-2,2¢-diylbis[1-(tert-butoxycarbon-
yl)prolinamides] (S)-3a and (R)-3a; General Procedure
Boc-L-proline 1 (454 mg, 2.2 mmol), DCC (474 mg, 2.2 mmol), and
DMAP (20 mg, 0.16 mmol) were dissolved in CH Cl (10 mL) and
1
H NMR (300 MHz, CDCl ): d = 1.27 [s, 18 H, C(CH ) ], 1.00–1.30
3
3 3
(
m, 2 H, CH ), 1.42–1.90 (series of m, 6 H, CH ), 2.30–2.65 (m, 2
2
2
H, CH ), 2.80–3.10 (m, 2 H, CH ), 3.90–4.20 (m, 2 H, CH), 7.05–
2
2
2
2
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

2
04
G.-N. Ma et al.
PAPER
1
7
.18 (m, 2 H, ArH), 7.20–7.35 (m, 2 H, ArH), 7.40–7.55 (m, 2 H,
H NMR (300 MHz, CDCl ): d = 0.85–1.10 (m, 2 H, CH ), 1.38 [s,
3
2
ArH), 7.65–8.13 (m, 6 H, ArH), 8.82 (br s, 2 H, NHCO).
9 H, C(CH ) ], 1.50–2.00 (m, 2 H, CH ), 1.79 (s, 3 H, CH ), 2.50–
3 3 2 3
+
2.65 (m, 1 H, CH), 2.85–3.10 (m, 1 H, CH), 3.90–4.20 (m, 1 H, CH),
MS (EI): m/z (%) = 678.4 (1.67) [M ], 409.2 (6.31), 267.1 (10.57),
6
4
.98–7.35 (m, 4 H, ArH), 7.38–7.47 (m, 2 H, ArH), 7.80–8.00 (m,
H, ArH), 8.03–8.15 (m, 2 H, ArH), 8.45 (br s, 1 H, NHCO).
7
0.1 (100).
2
¢-Acetamido-1,1¢-binaphthalen-2-ylamine (S)-5 and (R)-5;17
MS (EI): m/z (%) = 523.3 (8.10) [M ], 423.2 (6.77), 267.2 (59.51),
70.1 (100).
+
General Procedure
Ac O (208 mL, 2.2 mmol) was added to a mixture of (S)- or (R)-1,1¢-
2
binaphthyl-2,2¢-diamine [(S)-2 or (R)-2] (568 mg, 2.0 mmol),
1-(tert-Butoxycarbonyl)-N-[2¢-(tosylamino)-1,1¢-binaphthalen-
2-yl]prolinamides (S)-3c and (R)-3c; General Procedure
Boc-L-proline 1 (258 mg, 1.2 mmol), DCC (248 mg, 1.2 mmol), and
DMAP (20 mg, 0.16 mmol) were dissolved in CH Cl (10 mL) and
AcOH (1.2 mL, 20 mmol), and CH Cl (20 mL) with ice-cooling.
2
2
The mixture was stirred at r.t. overnight, and 2 M NaOH (0.2 mL)
was added until pH >7. The mixture was extracted with CH Cl and
2
2
2
2
the combined organic extracts were dried (anhyd MgSO ). The res-
the soln was cooled to 0 °C and stirred for 30 min. Then a soln of
4
idue obtained upon evaporation was purified by column chromatog-
raphy to afford (S)-5 or (R)-5 as white solids.
compound (S)-6 or (R)-6b (438 mg, 1.0 mmol) in CH Cl (10 mL)
2
2
1
7
was added dropwise over 30 min. When the addition was complete,
the mixture was warmed to r.t. and stirred for a further 12 h. Dicy-
clohexylurea was filtered off and the solvent was removed under re-
2
¢-(4-Tolylsulfonamido)-1,1¢-binaphthalen-2-ylamine (S)-6 and
R)-6;17 General Procedure
To a mixture of (S)- or (R)-1,1¢-binaphthyl-2,2¢-diamine [(S)-2 or
R)-2] (568 mg, 2.0 mmol) and pyridine (2.0 mL, 24 mmol) in
CH Cl (15 mL) was added dropwise a soln of TsCl (420 mg, 2.2
(
duced pressure. Then, H O (5 mL) was added and the product was
2
extracted with EtOAc (3 × 10 mL). The combined organic layers
(
were washed consecutively with 1.0 M KHSO (1 × 25 mL), H O
4
2
(1 × 25 mL), aq 10% NaHCO (1 × 25 mL), and H O (1 × 25 mL)
2
2
3
2
mmol) in CH Cl (5 mL). The mixture was stirred at r.t. for 12 h and
and dried (anhyd Na SO ). The solvent was evaporated to provide
2
2
2 4
then it was washed with 5% HCl (3 × 10 mL) and the separated or-
(S)-3c and (R)-3c, which were used for the next reaction without
further purification.
ganic layer was dried (anhyd MgSO ). The solvent was removed
4
under reduced pressure and the residue was purified by flash col-
1
7
umn chromatography (silica gel) to give (S)-6 or (R)-6 as white
solids.
N¢-Tosyl-Substituted 1-(tert-Butoxycarbonyl)prolinamide (S)-
3c
White solid; yield: 360 mg (57%); mp 165–168 °C.
N-(2¢-Acetamido-1,1¢-binaphthalen-2-yl)-1-(tert-butoxycarbon-
yl)prolinamides (S)-3b and (R)-3b; General Procedure
20
[
a]D –69.1 (c 1.045, CHCl3).
IR (film): 3333, 2977, 1697, 1621, 1502, 1476, 1452, 1367, 1163,
091, 984, 814, 744, 662 cm .
Boc-L-proline 1 (258 mg, 1.2 mmol), DCC (248 mg, 1.2 mmol), and
DMAP (20 mg, 0.16 mmol) were dissolved in CH Cl (10 mL) and
–
1
1
1
2
2
the soln was cooled to 0 °C and stirred for 30 min. A soln of (S)-5
or (R)-5 (325 mg, 1.0 mmol) in CH Cl (10 mL) was added drop-
H NMR (300 MHz, CDCl ): d = 1.32 [s, 9 H, C(CH ) ], 1.50–2.00
(m, 4 H, CH ), 2.37 (s, 3 H, CH ), 2.75–2.98 (m, 1 H, CH), 3.20–
3
3 3
2
2
2
3
wise over 30 min. When the addition was complete, the mixture was
warmed to r.t. and stirred for a further 12 h. Dicyclohexylurea was
filtered off and the solvent was removed under reduced pressure.
3
.70 (m, 1 H, CH), 4.00–4.20 (m, 1 H, CH), 6.25–6.54 (m, 2 H,
ArH), 6.85–7.24 (m, 2 H, ArH), 7.38–7.51 (m, 6 H, ArH), 7.80–8.00
m, 4 H, ArH), 8.03 (d, J = 8.7 Hz, 1 H, ArH), 8.46 (d, J = 8.7 Hz,
1 H, ArH), 8.67 (br s, 1 H, NHCO).
(
Then, H O (5 mL) was added and the product was extracted with
2
EtOAc (3 × 10 mL). The combined organic extracts were washed
+
MS (EI): m/z (%) = 635.2 (2.73) [M ], 438.1 (10.27), 311.1 (100),
67.1 (27.69), 70.1 (33.72).
consecutively with 1.0 M KHSO (1 × 25 mL), H O (1 × 25 mL), aq
4
2
2
1
0% NaHCO (1 × 25 mL), and H O (1 × 25 mL) and dried (anhyd
3
2
Na SO ). The solvent was evaporated to provide (S)-3b and (R)-3b,
2
4
N¢-Tosyl-Substituted 1-(tert-Butoxycarbonyl)prolinamide (R)-
3
which were used in the next reaction without further purification.
c
White solid; yield: 570 mg (89%); mp 203–204 °C.
N¢-Acetyl-Substituted 1-(tert-Butoxycarbonyl)prolinamide
2
0
(
S)-3b
[a]
D
–46.7 (c 1.175, CHCl ).
3
White solid; yield: 490 mg (91%); mp 186–189 °C.
IR (film): 3356, 2977, 1697, 1596, 1501, 1429, 1400, 1367, 1164,
20
–1
[
a]D –52.5 (c 0.33, CHCl3).
1091, 976, 815, 748, 662 cm .
1H NMR (300 Hz, CDCl
(m, 4 H, CH ), 2.38 (s, 3 H, CH
3
): d = 1.32 [s, 9 H, C(CH
) ], 1.69–2.06
3 3
), 2.60–2.84 (m, 1 H, CH), 2.95–
IR (film): 3262, 3055, 2977, 2932, 2879, 1690, 1394, 1163, 1124,
3
–1
1
089, 818, 735 cm .
2
1
3.20 (m, 1 H, CH), 3.95–4.20 (m, 1 H, CH), 6.25–6.54 (m, 2 H,
ArH), 6.85–7.24 (m, 2 H, ArH), 7.38–7.51 (m, 6 H, ArH), 7.85–8.05
H NMR (300 MHz, CDCl ): d = 1.10–1.50 (m, 2 H, CH ), 1.30 [s,
3
2
9
2
6
2
H, C(CH ) ], 1.50–2.00 (m, 2 H, CH ), 1.74 (s, 3 H, CH ), 2.50–
3 3 2 3
(m, 4 H, ArH), 8.08 (d, J = 8.7 Hz, 1 H, ArH), 8.58 (d, J = 8.7 Hz,
.70 (s, 1 H, CH), 2.92–3.10 (m, 1 H, CH), 4.11–4.13 (m, 1 H, CH),
.98–7.10 (m, 2 H, ArH), 7.20–7.45 (m, 4 H, ArH), 7.45–7.58 (m,
H, ArH), 7.93–8.09 (m, 4 H, ArH), 8.48 (br s, 1 H, NHCO).
+
1
H, ArH), 8.67 (br s, 1 H, NHCO).
+
MS (EI): m/z (%) = 635.3 (0.34) [M ], 438.2 (12.95), 311.1 (100),
267.1 (35.94), 70.1 (41.18).
MS (EI): m/z (%) = 523.3 (4.04) [M ], 423.2 (4.91), 267.2 (57.04),
7
0.1 (100).
Removal of the tert-Butoxycarbonyl Protecting Group; General
Procedure
N¢-Acetyl-Substituted 1-(tert-Butoxycarbonyl)prolinamide (R)-
Compounds 3a–c (1.0 mmol) were dissolved in a mixed soln of
TFA–CH Cl (1:4, 8.0 mL), and the resulting soln was stirred at r.t.
3
b
2
2
White solid; yield: 454 mg (86%); mp 222–224 °C.
for 2 h. The mixture was basified with concd NH soln (pH >8) and
3
a
]
2
0
+
7
.
9
(
c
0
.
9
0
,
C
H
C
l
)
.
D
3
extracted with CH Cl (3 × 10 mL). The solvent was removed under
[
2
2
reduced pressure and the residue was purified by flash chromatog-
IR (film): 3442, 3321, 2915, 2848, 1622, 1580, 1535, 1088, 1046,
8
–1
raphy (silica gel, EtOAc–MeOH, 5:1) to yield compounds 4a–c. All
92, 641 cm .
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

PAPER
Binaphthylene Backbone L-Proline Diamides as Organocatalysts for Asymmetric Aldol Reactions
205
+
these pure compounds 4a–c were obtained by recrystallization
HRMS (EI): m/z [M ] calcd for C H N O : 423.1947; found:
2
7
25
3
2
(
CH Cl , hexane).
423.1947.
2
2
(
S)-N,N¢-1,1¢-Binaphthalene-2,2¢-diylbis(prolinamide) [(S)-4a]
(R)-N-(2¢-Acetamido-1,1¢-binaphthalen-2-yl)prolinamide [(R)-
4b]
White solid; yield: 420 mg (89%); mp 240–241 °C.
2
0
White solid; yield: 360 mg (85%); mp 125–127 °C.
[
a]D –167.3 (c 1.02, CHCl3).
2
0
[
a]D +69.9 (c 1.02, CHCl3).
IR (film): 3338, 3215, 2965, 2869, 1678, 1594, 1501, 1426, 1344,
332, 1150, 868, 818, 776, 750 cm .
–
1
1
1
IR (film): 3274, 2970, 1686, 1677, 1655, 1597, 1500, 1460, 1276,
–
1
820, 750 cm .
H NMR (300 MHz, CDCl ): d = 0.82–0.96 (m, 2 H, CH ), 1.20–
.30 (m, 2 H, CH ), 1.55–1.68 (m, 2 H, CH ), 1.76–1.86 (m, 4 H,
CH), 2.10–2.38 (m, 2 H, CH ), 3.54 (dd, J = 4.2, 9.6 Hz, 2 H, CH),
3
2
1
1
H NMR (300 MHz, CDCl ): d = 0.95–1.10 (m, 1 H, CH ), 1.25–
2
2
3
2
1.35 (m, 1 H, CH ), 1.40–1.55 (m, 1 H, CH ), 1.65 (s, 3 H, CH ),
2
2
2
3
7
.17 (d, J = 8.4 Hz, 2 H, ArH), 7.25 (t, J = 7.5 Hz, 2 H, ArH), 7.39
1.68–1.82 (m, 1 H, CH ), 1.74 (s, 1 H, NH), 1.95–2.08 (m, 1 H,
2
(
t, J = 7.5 Hz, 2 H, ArH), 7.91 (d, J = 8.4 Hz, 2 H, ArH), 8.03 (d,
CH ), 2.35–2.50 (m, 1 H, CH ), 3.43 (dd, J = 4.5, 9.6 Hz, 1 H, CH),
2
2
J = 9.0 Hz, 2 H, ArH), 8.80 (d, J = 9.0 Hz, 2 H, ArH), 9.69 (s, 2 H,
NHCO).
6.91 (d, J = 8.4 Hz, 1 H, ArH), 7.04 (s, 1 H, NH), 7.05 (d, J = 8.7
Hz, 1 H, ArH), 7.08–7.20 (m, 2 H, ArH), 7.25–7.35 (m, 2 H, ArH),
7.81 (t, J = 8.1 Hz, 2 H, ArH), 7.92 (dd, J = 9.0, 12.6 Hz, 2 H, ArH),
1
3
C NMR (75 MHz, CDCl ): d = 25.6, 30.5, 46.0, 60.4, 119.0,
3
8
.44 (d, J = 9.0 Hz, 1 H, ArH), 8.44 (d, J = 9.0 Hz, 1 H, ArH), 9.51
1
19.4, 124.8, 125.1, 126.8, 128.1, 129.5, 130.7, 132.2, 134.9, 173.9.
(br s, 1 H, NHCO).
+
MS (EI): m/z (%) = 478.2 (2.57) [M ], 409.2 (13.78), 284.1 (13.21),
1
3
C NMR (75 MHz, CDCl ): d = 24.3, 25.5, 30.4, 46.4, 60.3, 120.5,
3
7
0.1 (100).
1
21.1, 121.3, 121.7, 124.8, 124.96, 124.98, 125.3, 126.7, 127.1,
Anal. Calcd for C H N O : C, 75.29, H, 6.32, N, 11.71. Found: C,
3
0
30
4
2
127.9, 128.1, 129.1, 129.9, 130.8, 131.2, 132.2, 132.3, 134.6, 134.9,
68.4, 174.3.
7
5.12, H, 6.38, N, 11.54.
1
+
MS (EI): m/z (%) = 423.2 (9.61) [M ], 326.1 (11.24), 267.1 (52.63),
(
R)-N,N¢-1,1¢-Binaphthalene-2,2¢-diylbis(prolinamide) [(R)-4a]
1
43.1 (8.66), 70.1 (100).
White solid; yield: 383 mg (80%); mp 225–228 °C.
+
20
HRMS (EI): m/z [M ] calcd for C27
H
25
N
3
O
2
: 423.1947; found:
[
a]D –3.7 (c 0.55, CHCl3).
4
23.1948.
IR (film): 3339, 3212, 2914, 2867, 1685, 1595, 1502, 1453, 1428,
1
–
1
261, 1089, 821, 750 cm .
(
S)-N-[2¢-(Tosylamino)-1,1¢-binaphthalen-2-yl]prolinamide
1
[(S)-4c]
H NMR (300 MHz, CDCl ): d = 1.25–1.30 (m, 2 H, CH ), 1.35–
3
2
White solid; yield: 470 mg (88%); mp 191–192 °C.
1
.55 (m, 2 H, CH ), 1.60–1.80 (m, 4 H, CH ), 2.20–2.28 (m, 2 H,
2
2
CH ), 2.52–2.61 (m, 2 H, CH), 3.52 (dd, J = 4.2, 9.3 Hz, 2 H, CH),
7
(
J = 9.0 Hz, 2 H, ArH), 8.77 (d, J = 9.0 Hz, 2 H, ArH), 9.69 (s, 2 H,
NHCO).
20
2
[a]D –205.2 (c 1.04, CHCl3).
.13 (d, J = 8.4 Hz, 2 H, ArH), 7.26 (t, J = 7.5 Hz, 2 H, ArH), 7.41
t, J = 7.5 Hz, 2 H, ArH), 7.93 (d, J = 7.5 Hz, 2 H, ArH), 8.04 (d,
IR (film): 3333, 3193, 3053, 2876, 1687, 1501, 1468, 1429, 1166,
–
1
1
092, 976, 814, 748, 663 cm .
1
H NMR (300 MHz, CDCl ): d = 0.82–0.95 (m, 1 H, CH ), 1.00–
3 2
1
3
1.35 (m, 1 H, CH
), 1.40–1.65 (m, 1 H, CH), 1.57 (br s, 1 H, NH),
2
C NMR (75 MHz, CDCl ): d = 25.6, 30.6, 46.6, 60.5, 119.6,
3
1
.78–2.05 (m, 2 H, CH ), 2.34 (s, 3 H, CH ), 2.50–2.60 (m, 1 H,
2
3
1
19.7, 124.8, 125.1, 126.8, 128.1, 129.5, 130.8, 132.6, 135.0, 173.6.
CH ), 3.50 (dd, J = 4.5, 9.3 Hz, 1 H, CH), 6.50 (d, J = 8.4 Hz, 1 H,
2
+
MS (EI): m/z (%) = 478.2 (2.21) [M ], 409.2 (7.84), 284.1 (9.50),
7
ArH), 6.85–7.05 (m, 4 H, ArH), 7.15–7.25 (m, 1 H, ArH), 7.35–7.42
0.1 (100).
(m, 4 H, ArH), 7.83–7.95 (m, 2 H, m ArH), 7.98 (d, J = 9.3 Hz, 1 H,
+
ArH), 8.03 (d, J = 9.3 Hz, 1 H, ArH), 8.14 (d, J = 8.7 Hz, 1 H, ArH),
HRMS (EI): m/z [M ] calcd for C H N O : 478.2369; found:
4
3
0
30
4
2
8
.78 (d, J = 8.7 Hz, 1 H, ArH), 9.69 (br s, 1 H, NHCO).
78.2357.
1
3
C NMR (75 MHz, CDCl ): d = 21.4, 25.8, 30.5, 46.6, 60.5, 117.5,
3
(
S)-N-(2¢-Acetamido-1,1¢-binaphthalen-2-yl)prolinamide [(S)-
b]
White solid; yield: 380 mg (90%); mp 166–167 °C.
1
1
1
18.7, 119.7, 120.0, 124.4, 124.6, 125.1, 125.3, 126.9, 127.2, 127.9,
28.1, 129.4, 129.9, 130.3, 130.6, 130.8, 132.1, 132.6, 133.6, 135.4,
35.9, 143.7, 173.9.
4
[
a
]
2
0
–
1
2
4
.
0
(
c
1
.
0
4
,
C
H
C
l
)
.
+
D
3
MS (EI): m/z (%) = 535.2 (1.09) [M ], 438.1 (7.97), 311.1 (100),
2
83.1 (14.84), 267.1 (26.05), 70.1 (51.57).
IR (film): 3252, 2956, 2926, 1671, 1594, 1500, 1449, 1426, 1276,
–1
8
19, 749 cm .
+
HRMS (EI): m/z [M ] calcd for C H N O S: 535.1930; found:
535.1927.
3
2
29
3
3
1
H NMR (300 MHz, CDCl ): d = 0.82–0.95 (m, 1 H, CH ), 1.20–
3
2
1
1
.35 (m, 1 H, CH ), 1.68–1.74 (m, 2 H, CH ), 1.76 (s, 3 H, CH ),
2
2
3
(
[
R)-N-[2¢-(Tosylamino)-1,1¢-binaphthalen-2-yl]prolinamide
(R)-4c]
.79–1.96 (m, 1 H, CH ), 1.80 (s, 1 H, NH), 2.30–2.45 (m, 1 H,
2
CH ), 3.52 (dd, J = 4.5, 9.6 Hz, 1 H, CH), 7.01 (s, 1 H, NHCOCH ),
2
3
White solid; yield: 430 mg (81%); mp 152–155 °C.
7
7
.03 (d, J = 8.7 Hz, 1 H, ArH), 7.16 (d, J = 8.7 Hz, 1 H, ArH), 7.18–
.32 (m, 2 H, ArH), 7.36–7.45 (m, 2 H, ArH), 7.91 (dd, J = 4.8, 7.8
20
[
a]D –4.7 (c 1.045, CHCl3).
Hz, 2 H, ArH), 8.03 (dd, J = 6.0, 9.0 Hz, 2 H, ArH), 8.50 (d, J = 9.0
Hz, 1 H, ArH), 8.70 (d, J = 9.0 Hz, 1 H, ArH), 9.74 (s, 1 H, NHCO).
IR (film): 3333, 3193, 3052, 2911, 1682, 1594, 1504, 1454, 1469,
1
–
1
429, 1315, 1166, 1091, 976, 814, 664 cm .
1
3
C NMR (75 MHz, CDCl ): d = 24.2, 25.1, 30.4, 46.0, 60.3, 119.0,
3
1
H NMR (300 MHz, CDCl ): d = 1.25–1.30 (m, 1 H, CH ), 1.45–
3
2
1
1
1
20.0, 120.6, 121.3, 124.6, 124.9, 125.2, 126.8, 127.1, 127.9, 128.2,
29.2, 129.8, 130.7, 130.9, 132.10, 132.12, 134.8, 135.0, 168.7,
74.1.
1
2
.70 (m, 1 H, CH ), 1.60 (br s, 1 H, NH), 1.80–2.03 (m, 2 H, CH ),
2
2
.30–2.50 (m, 1 H, CH ), 2.34 (s, 3 H, CH ), 2.55–2.68 (m, 1 H,
2
3
CH ), 3.50 (dd, J = 4.5, 9.0 Hz, 1 H, CH), 6.54 (d, J = 8.4 Hz, 1 H,
ArH), 6.85–7.05 (m, 4 H, ArH), 7.15–7.25 (m, 1 H, ArH), 7.30–7.45
2
+
MS (EI): m/z (%) = 423.2 (10.79) [M ], 326.1 (12.33), 267.1
(66.19), 143.1 (9.88), 70.1 (100).
(
m, 4 H, ArH), 7.85–7.90 (m, 2 H, ArH), 7.99 (d, J = 9.3 Hz, 1 H,
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

2
06
G.-N. Ma et al.
PAPER
ArH), 8.05 (d, J = 9.3 Hz, 1 H, ArH), 8.16 (d, J = 9.0 Hz, 1 H, ArH),
4-(2-Chlorophenyl)-4-hydroxybutan-2-one (8e)
Yield: 89.0 mg (91%). HPLC analysis (Chiralpak AD-H, hexane–
8
.77 (d, J = 9.0 Hz, 1 H, ArH), 9.64 (br s, 1 H, NHCO).
1
3
i-PrOH, 98:2, 1.0 mL/min, 220 nm, 20 °C): t (R, major) = 14.84
R
C NMR (75 MHz, CDCl ): d = 21.4, 25.8, 30.5, 46.6, 60.5, 117.5,
3
min and t (S, minor) = 11.01 min; 92% ee.
R
1
1
1
18.7, 119.7, 120.0, 124.4, 124.6, 125.1, 125.3, 126.9, 127.2, 127.9,
28.1, 129.4, 129.9, 130.3, 130.6, 130.8, 132.1, 132.6, 133.6, 135.4,
35.9, 143.7, 173.9.
2
0
[a]D +97.4 (c 1.15, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 2.21 (s, 3 H, CH ), 2.68 (dd,
3
3
+
MS (EI): m/z (%) = 535.2 (3.96) [M ], 438.1 (12.10), 311.1 (100),
J = 9.6, 17.7 Hz, 1 H, CH ), 2.96 (d, J = 9.6 Hz, 1 H, CH ), 3.45 (dd,
2
2
2
83.1 (13.60), 267.1 (9.48), 70.1 (6.26).
1 H, OH), 5.50 (d, J = 9.6 Hz, 1 H, CH), 7.15–7.40 (m, 3 H, ArH),
7.61 (d, J = 7.8 Hz, 1 H, ArH).
+
HRMS (EI): m/z [M ] calcd for C H N O S: 535.1930; found:
3
2
29
3
3
5
35.1934.
4
-(4-Bromophenyl)-4-hydroxybutan-2-one (8f)
Yield: 73.0 mg (60%). HPLC analysis (Chiralpak AS-H, hexane–
Aldol Products 8a–g, 9a–g, and 10; General Procedure
i-PrOH, 80:20, 1.0 mL/min, 220 nm, 20 °C): t (R, major) = 17.20
R
Bis(prolinamide) (S)-4a (24.0 mg, 0.05 mmol) was stirred in tolu-
ene (3.0 mL), ketone (such as acetone, cyclopentanone, or cyclo-
hexanone) (0.5 mL), then AcOH (4.0 mL) were added into the soln.
The mixture was stirred at –40 °C for 30 min. The corresponding
arylaldehyde 7 (0.5 mmol) was added and the mixture was stirred
min and t (S, minor) = 23.19 min; 76% ee.
R
2
0
[a]D +31.0 (c 0.525, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 2.01 (s, 3 H, CH ), 2.57 (dd,
3
3
J = 3.6, 17.4 Hz, 1 H, CH ), 2.70 (dd, J = 9.0, 17.4 Hz, 1 H, CH ),
2
2
for 48–72 h. The reaction was quenched with sat. NH Cl (10 mL)
4
3
.87 (br s, 1 H, OH), 4.93 (dd, J = 3.6, 9.0 Hz, 1 H, CH), 7.07 (d,
and extracted with EtOAc (3 × 10 mL). The combined organic ex-
J = 8.7 Hz, 2 H, ArH), 7.30 (d, J = 8.7 Hz, 2 H, ArH).
tracts were dried (anhyd Na SO ), filtered, and concentrated under
2
4
reduced pressure to give pure aldol adducts 8a–g, 9a–g, and 10 after
flash chromatography (silica gel, petroleum ether–EtOAc, 5:1~3:1).
4
-(4-Fluorophenyl)-4-hydroxybutan-2-one (8g)
Yield: 54.0 mg (57%). HPLC analysis (Chiralpak AD-H, hexane–
i-PrOH, 98:2, 1.0 mL/min, 220 nm, 20 °C): t (R, major) = 11.02
R
4
-Hydroxy-4-(4-nitrophenyl)butan-2-one (8a)
min and t (S, minor) = 12.78 min; 67% ee.
R
Yield: 86.0 mg (83%). HPLC analysis (Chiralpak AS-H, hexane–
i-PrOH, 80:20, 1.0 mL/min, 254 nm, 20 °C): t (R, major) = 25.91
min and t (S, minor) = 41.02 min; 93% ee.
[
a
]
2
0
+
2
0
.
4
(
c
0
.
5
0
,
C
H
C
l
)
.
D
3
R
1
R
H NMR (300 MHz, CDCl ): d = 2.18 (s, 3 H, CH ), 2.78 (dd,
3
3
20
J = 3.6, 17.4 Hz, 1 H, CH ), 2.86 (dd, J = 8.7, 17.4 Hz, 1 H, CH ),
[
a]D +59.4 (c 1.02, CHCl3).
2
2
3
7
.16 (br s, 1 H, OH), 5.10–5.14 (dd, J = 3.6, 8.7 Hz, 1 H, CH), 6.95–
.08 (m, 2 H, ArH), 7.25–7.38 (m, 2 H, ArH).
1
H NMR (300 MHz, CDCl ): d = 2.21 (s, 3 H, CH ), 2.80–2.89 (m,
3
3
2
7
H, CH ), 3.64 (br s, 1 H, OH), 5.26 (dd, J = 4.5, 7.5 Hz, 1 H, CH),
2
.53 (d, J = 9.0 Hz, 2 H, ArH), 8.21 (d, J = 9.0 Hz, 2 H, ArH).
2
-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (9a)
Yield: 112.0 mg (90%); ratio anti/syn 98:2.
4
-Hydroxy-4-(3-nitrophenyl)butan-2-one (8b)
[
a
]
2
0
+
1
0
.
2
(
c
1
.
0
0
,
C
H
C
l
)
.
Yield: 90.0 mg (86%). HPLC analysis (Chiralcel OJ-H, hexane–
D
3
i-PrOH, 80:20, 1.0 mL/min, 254 nm, 20 °C): t (R, major) = 18.10
R
anti-Diastereomer
HPLC analysis (Chiralcel OJ-H, hexane–i-PrOH, 70:30, 1.0 mL/
min, 254 nm, 20 °C): t (major) = 8.84 min and t (minor) = 10.67
min; 95% ee.
min and t (S, minor) = 21.09 min; 95% ee.
R
20
[
a]D +73.7 (c 1.05, CHCl3).
R
R
1
H NMR (300 MHz, CDCl ): d = 2.23 (s, 3 H, CH ), 2.87–2.89 (m,
3
3
2
7
H, CH ), 3.66 (br s, 1 H, OH), 5.26 (dd, J = 4.5, 7.5 Hz, 1 H, CH),
1
2
H NMR (300 MHz, CDCl ): d = 1.30–1.85 (series of m, 5 H, CH ),
3
2
.53 (t, J = 8.1 Hz, 1 H, ArH), 7.70 (d, J = 7.5 Hz, 1 H, ArH), 8.13
2
.05–2.20 (m, 1 H, CH ), 2.25–2.55 (m, 2 H, CH ), 2.58–2.68 (m, 1
2
2
(
d, J = 8.1 Hz, 1 H, ArH), 8.24 (s, 1 H, ArH).
H, CH), 4.09 (br s, 1 H, OH), 4.89 (d, J = 8.4 Hz, 1 H, CH), 7.49 (d,
J = 8.7 Hz, 2 H, ArH), 8.19 (d, J = 8.7 Hz, 2 H, ArH).
4
-Hydroxy-4-(2-nitrophenyl)butan-2-one (8c)
Yield: 90.0 mg (86%). HPLC analysis (Chiralpak AS-H, hexane–
syn-Diastereomer
HPLC analysis (Chiralcel OJ-H, hexane–i-PrOH, 70:30, 1.0 mL/
min, 254 nm, 20 °C): t = 9.85 min and t = 15.14 min.
i-PrOH, 70:30, 1.0 mL/min, 254 nm, 20 °C): t (R, major) = 10.92
R
min and t (S, minor) = 9.98 min; 98% ee.
R
R
R
20
[
a]D +72.9 (c 1.02, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 1.30–1.85 (series of m, 5 H, CH ),
3
2
1
H NMR (300 MHz, CDCl ): d = 2.22 (s, 3 H, CH ), 2.85–2.90 (m,
2.05–2.20 (m, 1 H, CH ), 2.25–2.55 (m, 2 H, CH ), 2.58–2.68 (m, 1
3
3
2
2
2
7
8
H, CH ), 3.71 (br s, 1 H, OH), 5.26 (dd, J = 3.6, 7.2 Hz, 1 H, CH),
H, CH), 5.47 (d, J = 1.5 Hz, 1 H, CH), 7.48 (d, J = 8.8 Hz, 2 H,
ArH), 8.20 (d, J = 8.8 Hz, 2 H, ArH).
2
.52 (t, J = 7.8 Hz, 1 H, ArH), 7.70 (d, J = 7.8 Hz, 1 H, ArH), 8.10–
.14 (m, 1 H, ArH), 8.24 (m, 1 H, ArH).
2
-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone (9b)
4
-(4-Chlorophenyl)-4-hydroxybutan-2-one (8d)
Yield: 103.0 mg (83%); ratio anti/syn 98:2.
Yield 68.0 mg (67%). HPLC analysis (Chiralpak AS-H, hexane–
20
[
a]D +29.6 (c 1.06, CHCl3).
i-PrOH, 90:10, 1.0 mL/min, 220 nm, 20 °C): t (R, major) = 25.91
R
min and t (S, minor) = 41.02 min; 81% ee.
R
anti-Diastereomer
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 254 nm, 20 °C): t (major) = 31.95 min and t (minor) = 41.13
min; 95% ee.
20
[
a]D +98.8 (c 1.035, CHCl3).
1
R
R
H NMR (300 MHz, CDCl ): d = 2.19 (s, 3 H, CH ), 2.75–2.85 (m,
3
3
2
7
H, CH ), 3.07 (br s, 1 H, OH), 5.11 (dd, J = 3.9, 8.4 Hz, 1 H, CH),
2
1
.26–7.33 (m, 4 H, ArH).
H NMR (300 MHz, CDCl ): d = 1.30–1.85 (series of m, 5 H, CH ),
3 2
2
.05–2.20 (m, 1 H, CH ), 2.30–2.55 (m, 2 H, CH ), 2.58–2.68 (m, 1
2
2
H, CH), 4.12 (br s, 1 H, OH), 4.89 (d, J = 8.4 Hz, 1 H, CH), 7.52 (t,
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

PAPER
Binaphthylene Backbone L-Proline Diamides as Organocatalysts for Asymmetric Aldol Reactions
207
1
J = 8.1 Hz, 1 H, ArH), 7.67 (d, J = 8.1 Hz, 1 H, ArH), 8.16 (d,
J = 8.1 Hz, 1 H, ArH), 8.20 (s, 1 H, ArH).
H NMR (300 MHz, CDCl ): d = 1.20–1.35 (m, 1 H, CH ), 1.40–
3
2
1.85 (m, 4 H, CH ), 2.00–2.15 (m, 1 H, CH ), 2.25–2.50 (m, 2 H,
2
2
CH ), 2.55–2.65 (m, 1 H, CH), 3.99 (br s, 1 H, OH), 4.74 (d, J = 8.4
2
syn-Diastereomer
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 254 nm, 20 °C): t = 25.48 min and t = 28.74 min.
Hz, 1 H, CH), 7.17 (d, J = 8.4 Hz, 2 H, ArH), 7.47 (d, J = 8.4 Hz, 2
H, ArH).
R
R
1
syn-Diastereomer
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 220 nm, 20 °C): t = 9.17 min and t = 10.92 min.
H NMR (300 MHz, CDCl ): d = 1.46–1.90 (series of m, 5 H, CH ),
3
2
2
.05–2.18 (m, 1 H, CH ), 2.30–2.55 (m, 2 H, CH ), 2.60–2.70 (m, 1
2
2
R
R
H, CH), 3.20 (br s, 1 H, OH), 5.48 (d, J = 2.4 Hz, 1 H, CH), 7.53 (t,
J = 7.8 Hz, 1 H, ArH), 7.68 (d, J = 7.8 Hz, 1 H, ArH), 8.13 (d,
J = 7.8 Hz, 1 H, ArH), 8.19 (s, 1 H, s, ArH).
1
H NMR (300 MHz, CDCl ): d = 1.40–2.05 (series of m, 5 H, CH ),
3
2
2.05–2.20 (m, 1 H, CH ), 2.30–2.65 (m, 3 H, CH), 3.09 (br s, 1 H,
2
OH), 5.33 (d, J = 2.1 Hz, 1 H, CH), 7.18 (d, J = 8.4 Hz, 2 H, ArH),
7.45 (d, J = 8.4 Hz, 2 H, ArH).
2
-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone (9c)
Yield: 103.0 mg (83%); ratio anti/syn 98:2.
20
2-[(4-Fluorophenyl)(hydroxy)methyl]cyclohexanone (9f)
Yield: 68.0 mg (61%); ratio anti/syn 92:8.
[
a]D +25.4 (c 1.02, CHCl3).
2
0
anti-Diastereomer
HPLC analysis (Chiralcel OD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 254 nm, 20 °C): t (major) = 21.24 min and t (minor) = 31.18
[a]D +17.7 (c 1.045, CHCl3).
anti-Diastereomer
R
R
min; 90% ee.
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
1
min, 220 nm, 20 °C): t (minor) = 12.29 min and t (major) = 13.50
min; 92% ee.
R
R
H NMR (300 MHz, CDCl ): d = 1.35–1.85 (series of m, 5 H, CH ),
3
2
2
.05–2.20 (m, 1 H, CH ), 2.30–2.50 (m, 2 H, CH ), 2.55–2.68 (m, 1
2
2
1
H, CH), 4.09 (br s, 1 H, OH), 4.89 (d, J = 8.4 Hz, 1 H, CH), 7.53 (t,
J = 7.8 Hz, 1 H, ArH), 7.68 (d, J = 7.8 Hz, 1 H, ArH), 8.15–8.19
H NMR (300 MHz, CDCl ): d = 1.15–1.35 (m, 1 H, CH ), 1.40–
3 2
1.85 (m, 4 H, CH ), 2.05–2.15 (m, 1 H, CH ), 2.30–2.65 (m, 3 H,
2
2
(m, 1 H, ArH), 8.17–8.21 (m, 1 H, ArH).
CH), 4.01 (br s, 1 H, OH), 4.77 (d, J = 8.7 Hz, 1 H, CH), 7.03 (t,
J = 8.7 Hz, 2 H, ArH), 7.27–7.31 (m, 2 H, ArH).
syn-Diastereomer
HPLC analysis (Chiralcel OD-H, hexane–i-PrOH, 90:10, 1.0 mL/
syn-Diastereomer
min, 254 nm, 20 °C): t = 18.15 min and t = 18.75 min.
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
R
R
1
min, 220 nm, 20 °C): t = 8.23 min and t = 9.42 min.
R R
H NMR (300 MHz, CDCl ): d = 1.45–1.90 (series of m, 5 H, CH ),
3
2
1
2
.05–2.20 (m, 1 H, CH ), 2.30–2.55 (m, 2 H, CH ), 2.60–2.70 (m, 1
H NMR (300 MHz, CDCl ): d = 1.45–1.75 (series of m, 5 H, CH ),
3 2
2
2
H, CH), 3.20 (br s, 1 H, OH), 5.47 (d, J = 2.1 Hz, 1 H, CH), 7.51 (t,
J = 7.8 Hz, 1 H, ArH), 7.65 (d, J = 7.8 Hz, 1 H, ArH), 8.09–8.11 (m,
1
2.05–2.18 (m, 1 H, CH ), 2.30–2.50 (m, 2 H, CH ), 2.55–2.65 (m, 1
2
2
H, CH), 3.06 (br s, 1 H, OH), 5.36 (d, J = 2.1 Hz, 1 H, CH), 7.03 (t,
J = 8.7 Hz, 2 H, ArH), 7.24–7.29 (m, 2 H, ArH).
H, ArH), 8.12–8.18 (m, 1 H, ArH).
2
-[(4-Chlorophenyl)(hydroxy)methyl]cyclohexanone (9d)
2-[Hydroxy(phenyl)methyl]cyclohexanone (9g)
Yield: 46 mg (45%); ratio anti/syn 97:3.
Yield: 85.0 mg (71%); ratio anti/syn 97:3.
20
20
[
a]D +22.6 (c 1.005, CHCl3).
[a]D +26.5 (c 0.40, CHCl3).
anti-Diastereomer
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 220 nm, 20 °C): t (minor) = 12.78 min and t (major) = 14.73
anti-Diastereomer
HPLC analysis (Chiracel OD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 220 nm, 20 °C): t (minor) = 18.5 min and t (major) = 27.5
R
R
R
R
min; 98% ee.
min; 80% ee.
1
1
H NMR (300 MHz, CDCl ): d = 1.25–1.85 (series of m, 5 H, CH ),
H NMR (300 MHz, CDCl ): d = 1.20–1.40 (m, 1 H, CH ), 1.45–
3
2
3
2
2
.00–2.15 (m, 1 H, CH ), 2.25–2.50 (m, 2 H, CH ), 2.55–2.65 (m, 1
1.82 (m, 4 H, CH ), 2.05–2.20 (m, 1 H, CH ), 2.30–2.58 (m, 2 H,
2
2
2
2
H, CH), 4.00 (br s, 1 H, OH), 4.76 (d, J = 8.7 Hz, 1 H, CH), 7.24 (d,
J = 8.4 Hz, 2 H, ArH), 7.31 (d, J = 8.4 Hz, 2 H, ArH).
CH), 2.60–2.70 (m, 1 H, CH), 4.79 (d, J = 8.7 Hz, 1 H, CH), 7.31–
7.36 (m, 5 H, ArH).
syn-Diastereomer
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 220 nm, 20 °C): t 8.39 min and t 9.82 min.
syn-Diastereomer
HPLC analysis (Chiralcel OD-H, hexane–i-PrOH, 90:10, 1.0 mL/
min, 220 nm, 20 °C): t = 14.8 min and t = 16.3 min.
R
R
R
R
1
1
H NMR (300 MHz, CDCl ): d = 1.25–1.85 (series of m, 5 H, CH ),
H NMR (300 MHz, CDCl ): d = 1.40–1.80 (m, 4 H, CH ), 2.05–
3 2
3
2
2
.00–2.15 (m, 1 H, CH ), 2.25–2.50 (m, 2 H, CH ), 2.55–2.65 (m, 1
2.20 (m, 1 H, CH ), 2.30–2.58 (m, 2 H, CH), 2.60–2.70 (m, 1 H,
2
2
2
H, CH), 5.36 (d, J = 2.4 Hz, 1 H, CH), 7.24 (d, J = 8.4 Hz, 2 H,
ArH), 7.31 (d, J = 8.4 Hz, 2 H, ArH).
CH), 5.39 (d, J = 2.4 Hz, 1 H, CH), 7.30–7.35 (m, 5 H, ArH).
2
-[Hydroxy(4-nitrophenyl)methyl]cyclopentanone (10)
2
-[(4-Bromophenyl)(hydroxy)methyl]cyclohexanone (9e)
Yield: 100.0 mg (84%); ratio anti/syn 30:70.
Yield: 98.0 mg (70%); ratio anti/syn 95:5.
20
[
a]D +98.2 (c 1.025, CHCl3).
20
[
a]D +17.3 (c 1.03, CHCl3).
syn-Diastereomer
anti-Diastereomer
HPLC analysis (Chiralpak AD-H, hexane–i-PrOH, 90:10, 1.0 mL/
HPLC analysis (Chiralpak AS-H, hexane–i-PrOH, 85:15, 0.8 mL/
min, 254 nm, 20 °C): t (major) = 24.49 min and t (minor) = 79.12
R
R
min, 220 nm, 20 °C): t (minor) = 14.80 min and t (major) = 17.37
min; 81% ee.
R
R
min; 96% ee.
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York

2
08
G.-N. Ma et al.
PAPER
1
H NMR (300 MHz, CDCl ): d = 1.47–2.52 (series of m, 7 H, CH ),
(4) (a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395. (b) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386. (c) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F. III J. Am. Chem. Soc. 2001, 123, 5260.
(d) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3,
573. (e) Cordova, A.; Notz, W.; Barbas, C. F. III J. Org.
Chem. 2002, 67, 301. (f) 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.
3
2
2
.87 (br s, 1 H, OH), 5.41 (d, J = 3.0 Hz, 1 H, CH), 7.53 (d, J = 8.7
Hz, 2 H, ArH), 8.21 (d, J = 8.7 Hz, 2 H, ArH).
anti-Diastereomer
HPLC analysis (Chiralpak AS-H, hexane–i-PrOH, 85:15, 0.8 mL/
min, 254 nm, 20 °C): t (minor) = 27.45 min and t (major) = 37.17
min; 98% ee.
R
R
1
H NMR (300 MHz, CDCl ): d = 1.67–2.54 (series of m, 7 H, CH ),
3
2
(
5) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 32. (b) Northrup, A. B.; Mangion, I.
K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed.
4
.78 (s, 1 H, OH), 4.84 (d, J = 9.0 Hz, 1 H, CH), 7.54 (d, J = 8.7
Hz, 2 H, ArH), 8.21 (d, J = 8.7 Hz, 2 H, ArH).
2
004, 43, 2152.
(
6) (a) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjoerdgaard,
Acknowledgment
A.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 3703.
We thank the State Key Project of Basic Research (Project 973)
(
b) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
(No. G2000048007), Shanghai Municipal Committee of Science
K. A. Angew. Chem. Int. Ed. 2005, 44, 794. (c) Halland, N.;
Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A.
J. Am. Chem. Soc. 2004, 126, 4790.
and Technology (04JC14083), and the National Natural Science
Foundation of China (203900502, 20472096 and 20272069) for fi-
nancial support.
(
7) (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43, 1983.
(
b) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
8) Samanta, S.; Liu, L.; Dodda, R.; Zhao, C. G. Org. Lett. 2005,
, 5321.
References
(
(
7
(
1) The significance of organocatalysis is outlined in special
issues of (a) Acc. Chem. Res. 2004, 37, 487–637. (b) Adv.
Synth. Catal. 2004, 346, 1007–1249.
9) Chen, J. R.; Lu, H. H.; Li, X. Y.; Cheng, L.; Wan, J.; Xiao,
W. J. Org. Lett. 2005, 7, 4543.
10) Gryko, D.; Kowalczyk, B.; Zawadzki, Ł. Synlett 2006, 1059.
(
(
(2) For reviews, see: (a) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis: From Biomimetic Concepts to
11) As we were carrying out this research, Gryko and co-
5
workers reported similar results. However, we have found
Applications in Asymmetric Synthesis; Wiley-VCH:
Weinheim, 2005. (b) Gröger, H.; Wilken, J. Angew. Chem.
Int. Ed. 2001, 40, 529. (c) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (d) Yoon, T. P.; Jacobsen, E.
N. Science 2003, 299, 1691. (e) Dalko, P. I.; Moisan, L.
Angew. Chem. Int. Ed. 2001, 40, 3726. (f) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
3) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Fleming, I.; Heathcock, C. H., Eds.; Pergamon: Oxford,
that in the presence of AcOH at –40 °C in toluene, the
enantioselectivities and diastereoselectivities could be
improved significantly: (a) Wang, C.-J.; Shi, M. J. Org.
Chem. 2003, 68, 6229. (b) Wang, C.-J.; Shi, M. Eur. J. Org.
Chem. 2003, 68, 2823. (c) Shi, M.; Wang, C.-J. Adv. Synth.
Catal. 2003, 345, 971. (d) Shi, M.; Wang, C.-J.; Zhang, W.
Chem. Eur. J. 2004, 10, 5507.
(
(
(
(
(
(
12) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem.
Int. Ed. 2005, 44, 3055.
13) Miyano, S.; Nawa, M.; Mori, A.; Hashimoto, H. Bull. Chem.
Soc. Jpn. 1984, 57, 2171.
1991, 229.
14) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
1
2911.
15) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am.
Chem. Soc. 2003, 125, 16.
16) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006, 128,
734.
(
17) Wang, C. J.; Shi, M. Eur. J. Org. Chem. 2003, 15, 2823.
Synthesis 2007, No. 2, 197–208 © Thieme Stuttgart · New York