A highly efficient organocatalyst for direct Aldol reactions of ketones with aldedydes

Article abstract of DOI:10.1021/ja0510156

L-Proline amides derived from various chiral β-amino alcohols that bear substituents with various electron natures at their stereogenic centers are prepared and evaluated for catalyzing the direct Aldol reaction of 4-nitrobenzaldehyde with acetone. Cataly

Full text of DOI:10.1021/ja0510156

Published on Web 06/04/2005
A Highly Efficient Organocatalyst for Direct Aldol Reactions
of Ketones with Aldedydes
Zhuo Tang, Zhi-Hua Yang,† Xiao-Hua Chen, Lin-Feng Cun, Ai-Qiao Mi,
Yao-Zhong Jiang, and Liu-Zhu Gong*
Contribution from the Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan
ProVince, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
610041, China, and Graduate School of Chinese Academy of Sciences, Beijing, China
Received February 17, 2005; E-mail: gonglz@cioc.ac.cn
Abstract: L-Proline amides derived from various chiral â-amino alcohols that bear substituents with various
electron natures at their stereogenic centers are prepared and evaluated for catalyzing the direct Aldol
reaction of 4-nitrobenzaldehyde with acetone. Catalysts with strong electron-withdrawing groups are found
to exhibit higher catalytic activity and enantioselectivity than their analogues with electron-donating groups.
The presence of 2 mol % catalyst 4g significantly catalyzes the direct Aldol reactions of a wide range of
aldehydes with acetone and butanone, to give the â-hydroxy ketones with very high enantioselectivities
ranging from 96% to >99% ee. High diastereoselectivity of 95/5 was observed for the anti Aldol product
from the reaction of cyclohexanone, and excellent enantioselectivity of 93% ee was provided for anti Aldol
product from the reaction of cyclopentanone.
work by List and Barbas and their co-wokers.5c-e Since then,
L-proline6 and its structural analogues7-10 have been evaluated
Introduction
The Aldol reaction is considered one of the most important
carbon-carbon bond-forming reactions in organic synthesis. Its
great usefulness for building up natural products, in particular
those with polyoxygenated subunits,1 has promoted the rapid
evolution of efficient chiral catalysts.2 The direct Aldol reaction
is highly atom efficient,3 compared with well-established
processes using enol or enolate derivatives as the Aldol donor.2
Recently, the highly enantioselective direct Aldol reaction of
aldehydes with ketones in the presence of a catalytic amount
of bifunctional transition metal complexes has been reported.4
Although proline-catalyzed Robinson annulation appeared in the
early 1970s,5a,b the real breakthrough came from the pioneering
for use in asymmetric catalytic direct intermolecular Aldol
reactions. Although impressive results were observed for
R-branched aliphatic aldehydes, only fair enantioselectivities
were observed for the reactions of aromatic aldehydes with
acetone either by L-proline5c,d or its derivatives and structural
analogues,7,8 with the exception of an N-substituted proline
amide derived from (1S,2S)-1,2-diphenylaminoethanol9 and a
proline-derived N-sulfonylcarboxamine,10a which gave high
enantioselectivity for the para-substituted benzaldehydes. Thus
far, the organocatalysts that have been used for the direct Aldol
reaction of aldehydes with ketones are highly enantioselective
for a comparably narrow range of substrates. Nonetheless,
catalyst loading of as high as 20 or 30 mol % is usually required
† Visiting scholar from Sichuan University.
(1) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon:
Oxford, 1991; Vol. 2, p 229.
(6) For reviews, see: (a) List, B. Tetrahedron 2002, 58, 5573. (b) List, B.
Synlett 2001, 1675. (c) Alcaide, B.; Almendros, P. Angew. Chem. Int. Ed.
2003, 42, 858. (d) List, B. Acc. Chem. Res. 2004, 37, 548. (e) Notz, W.;
Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. For leading
literatures, see: (f) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798. (g) Co´rdova, A.; Notz, W.; Barbas, C. F., III. J.
Org. Chem. 2002, 67, 301. (h) Bøgevig, A.; Kumaragurubaran, N.;
Jørgensen, K. A. Chem. Commun. 2002, 620. (i) Pidathala, C.; Hoang, L.;
Vignola, N.; List, B. Angew. Chem. Int. Ed. 2003, 42, 2785. (j) Northrup,
A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem.
Int. Ed. 2004, 43, 2152. (l) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak,
B.; Co´rdova, A. Angew. Chem. Int. Ed. 2005, 44, 1343.
(7) (a) Hartikaa, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831.
(b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem. Int. Ed. 2004, 43, 1983. For review, see: (c) Saito, S.; Yamamoto,
H. Acc. Chem. Res. 2004, 37, 570.
(8) (a) Martin, H. J.; List, B. Synlett, 2003, 1901. (b) Kofoed, J.; Nielsen, J.;
Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445.
(2) For reviews, see: (a) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur.
J. 1998, 4, 1137. (b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(c) Carreira, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999;
Vol. III, Chapter 29.1. (d) Mahrwald, R. Chem. ReV. 1999, 99, 1095. (e)
Machajewski, T. D.; Wong, C.-H. Angew. Chem. Int. Ed. 2000, 39, 1352.
(f) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (g) Denmark,
S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432. (h) Palomo, C.;
Oiarbide, M.; Garc´ıa, J. M. Chem. Soc. ReV. 2004, 33, 65.
(3) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem.
Int. Ed. Engl. 1995, 34, 259.
(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.;
Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168. (c) Trost, B.
M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (d) Trost, B. M.; Ito, H.;
Siloff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. (e) Evans, D. A.; Downey,
C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706.
(9) (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.; Jiang,
F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5755.
(10) (a) Berkessel, A.; Koch, B.; Lex, J. AdV. Synth. Catal. 2004, 346, 1141.
(b) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S.
V. Org. Biomol. Chem. 2005, 3, 84.
(5) (a) Hojas, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b) Eder,
U.; Sauer, R.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496. (c)
List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122,
2395. (d) Sakthivel, K.; Notz, W.; Bui, T.; Barbas C. F., III. J. Am. Chem.
Soc. 2001, 123, 5260. (e) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122,
7386.
9
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J. AM. CHEM. SOC. 2005, 127, 9285-9289
9285

A R T I C L E S
Tang et al.
Results and Discussion
Preparation of New Organocatalysts. The synthetic route
to approach L-proline amides 4b-c, 4f, 4i, and 4l, which are
derived from optically pure 1,2-diphenyl-2-aminoethanols, was
reported previously.9
The preparation of L-proline amides substituted with cyclo-
hexyl groups (organocatalysts 4a, 4e, 4h, and 4k) started with
commercially available optically pure 1,2-diphenyl-2-aminoet-
Figure 1. L-Proline amides used for direct Aldol reactions previously.9b
Table 1. The Direct Aldol Reaction of p-Nitrobenzaldehyde with
Acetone Catalyzed by Organocatalysts 1-39b
11
hanols 6a-d. Hydrogenation of 6a-d catalyzed by Ru/Al2O3
under 100 atm of hydrogen afforded 1,2-dicyclohexyl-2-
aminoethanols 7a-d in 87-89% yields without loss of the
enantiomeric purity, which reacted with Cbz-proline in the
presence of stoichiometric amounts of ClCOOEt and triethy-
lamine to give corresponding amides 8a-d. Hydrogenolysis of
the crude amides 8a-d in the presence of 5% Pd-C deprotected
the N-Cbz group to provide 4a, 4e, 4h, and 4k in high yields
(77-87%, two steps from 7a-d) (Scheme 1).
The synthesis of L-proline amides 4d, 4g, 4j and 4m
commenced with optically pure 11a and 11b, respectively de-
rived from diethyl tartrates 9a and 9b (Scheme 2).12 Respective
treatment of diethyl epoxysuccinates 11a and 11b with sodium
azide in the presence of ammonium chloride in DMF provided
diastereomeric mixtures of 12a,b and 12c,d in high yields with
a diastereomeric ratio of 1:1. A crude diastereomeric mixture
of either 12a and 12b or 12c and 12d was directly hydrogenated
under 1 atm of hydrogen in the presence of 5% Pd-C to furnish
the diastereometric mixture of diethyl 2-amino-3-hydroxysuc-
cinates 13a and 13b or 13c and 13d. Each pure diastereomer
of diethyl 2-amino-3-hydroxysuccinate was obtained by careful
column chromatography. The optically pure diethyl 2-amino-
3-hydroxysuccinates 13a-d were respectively coupled with
Cbz-proline by action of EDCI, HOBt, and NMM in dichlo-
romethane to generate 14a-d. After a hydrogenolysis of crude
14a-d catalyzed by 5% Pd-C, the desired organocatalysts 4d,
4g, 4j, and 4m were obtained with 45-53% yields (two steps
from 13).
organo-
catalyst
yield
(%)b
ee
organo-
catalyst
yield
(%)b
ee
entry
(%)c
entry
(%)c
1
2
3
4
1a
1b
1c
2a
80
82
55
78
30
21
15
31
5
6
7
8
2b
2c
3a
3b
88
88
78
63
37
45
33
61
a The reaction was carried out in neat acetone with a concentration of
0.5 M. b Isolated yield based on the aldehyde. c The ee values were
determined by HPLC, and the configuration was assigned as R by
comparison of retention times.
to achieve a good isolated yield of the Aldol product.5c-e,8-10
Therefore, highly efficient chiral organocatalysts, which not only
show generally high enantioselectivity for a broad scope of
substrates but also allow for the use of low catalyst loading
(less than 5 mol %), are still limited, and further development
is required.
Previously, we discovered that secondary amides with N-alkyl
groups such as 1a-c (Figure 1) show lower enantioselectivities
than their analogues with N-aryl groups 2a-c (Table 1, entries
1-6). In particular, the enantioselectivity increases as the aryl
substituent of 2a-c varies from an electron-donating to an
electron-withdrawing group (entries 4-6). It is also interesting
to compare the results obtained with catalysts 3a and 3b, which
only differ in the electronic properties of the substituent bonding
to their R-carbon on the amino alcohol moiety. 3b containing
an ester function catalyzes the reaction much more enantio-
selectively than 3a, which bears an isopropyl group (entries 7
and 8).9b
On the basis of the above-mentioned observations, we
speculated that the positive effect of the ester group on the
catalytic performance of the organocatalyst might be due to the
electron-withdrawing property of the ester, which makes the
N-H more acidic, resulting in the formation of a stronger
hydrogen bond. If this speculation is generally correct, we
further hypothesize that new organocatalysts with improved
catalytic performance over those reported previously9 can be
reasonably obtained by tuning the electron property of the
substituent bonded to either the R- or â-carbon (R1 or R2) in
organic molecules of type 4 (Figure 2). To address this
hypothesis, in this study we examined the electron effect of the
substituent attached to either the R- or â-carbon on the amino
alcohol part of organocatalysts 4 (Figure 2) on catalytic
performance; as a result, we discovered a new highly efficient
organocatalyst for the direct Aldol reaction, which promotes
the direct Aldol reactions of a broad range of aldehydes with
ketones to generate â-hydroxy ketones with excellent enanti-
oselectivities by using <5 mol % catalyst loading.
The Direct Aldol Reaction of p-Nitrobenzaldehyde with
Acetone Catalyzed by Organocatalysts 4: Demonstration
of the Electronic Effect of Side Chain on the Catalytic
Performance. The L-proline amides 4a-g were first screened
for their ability to catalyze the model direct Aldol reaction of
p-nitrobenzaldehyde with acetone. As shown in Table 2, the
electron nature of the substituent strongly affects the enanti-
oselectivity of the reaction. The enantioselectivity tends to
increase as the substituent varies from an electron-donating
group to an electron-withdrawing group. For example, the use
of 4a as a catalyst leads to the formation of Aldol product 5a
in good yield but low enantioselectivity (entry 1). Catalyst 4b9
with two phenyl groups, which are more electron-withdrawing
than cyclohexyl groups, is more enantioselective than 4a (entry
2). The presence of a stronger electron-withdrawing substituent
such as an ester group at the R-carbon or both the R- and
â-carbons, as seen with catalysts 4c and 4d, results in consider-
ably enhanced results (entries 3 and 4). More significant cases
are the reactions catalyzed by 4e-g, among which 4g shows a
9
much higher level of stereocontrol than 4e and 4f (entries 5
(11) (a) Saito, S.; Bunya, N.; Inaba, M.; Moriwake, T.; Torii, S. Tetrahedron
Lett. 1985, 26, 5309. (b) Tong, P.-E.; Li, P.; Chan, A. S. C. Tetrahedron:
Asymmetry 2001, 12, 2301.
(12) Saito, S.; Komada, K.; Moriwake, T. Organic Syntheses; Wiley: New York,
Collect. Vol. IX, p 220.
9
9286 J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005

Organocatalyst for Direct Aldol Reactions
A R T I C L E S
Figure 2. L-Proline amides evaluated for catalyzing direct Aldol reactions of ketones with aldehydes in this study.
Scheme 1. Preparation of L-Proline Amides Substituted with Cyclohexyl Groupsa
a Reagents and conditions: (a) Ru/Al2O3, H2 (100 atm), 95% EtOH, 60 °C, 12 h, 87-89%; (b) ClCOOEt/Et3N; (c) H2 (1 atm), Pd/C, MeOH, 77-87%
(two steps).
Scheme 2. Preparation of L-Proline Amides Substituted with Ester Groupsa
a Reagents and conditions: (a) (1) HBr, HOAc; (2) EtOH, HCl; (b) NaOEt, EtOH; (c) NaN3, NH4Cl, DMF; (d) Pd/C (5%), H2, MeOH; (e) EDCI, HOBt,
NMM; (f) Pd/C (5%), H2, MeOH, 45-53% (two steps).
and 6), to give rise to 5a with 85% isolated yield and 87% ee
(entry 7). Then, the diastereomers 4h-m of organocatalysts 4a,b
and 4d-g were examined for catalyzing the model reaction,
once again resulting in that organocatalysts with a strongly
electron-withdrawing substituent show much higher catalytic
efficacy than those with electron-donating substituent (entries
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J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005 9287

A R T I C L E S
Tang et al.
Table 3. Study on the Scope and Limitation of Aldehydesa
Table 2. Organocatalysts 4 Catalyzed the Direct Aldol Reaction of
4-Nitrobenzaldehyde with Acetonea
yield
(%)b
ee
entry
product
R1
(%)c
organo-
catalyst
yield
(%)b
ee
organo-
catalyst
yield
(%)b
ee
entry
(%)c
entry
(%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
4-NO2C6H4
4-BrC6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
Ph
R-naphthyl
4-MeC6H4
4-t-BuC6H4
2,6-Cl2C6H3
4-CNC6H4
4-CF3C6H4
3,5-(CF3)2C6H4
t-Bu
62
41
84
99
60
68
63
65
45
60
56
70
60
71
75
80
99
96
99
96
97
98
97
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
51
77
76
81
53
89
85
59
15
9
10
11
12
13
14
15
4i
4j
76
81
75
63
80
60
62
64d
75e
17
44d
67d
72e
15
4k
4l
4m
4g
4g
49d
67e
95e,f
99e,g
69d
87e
12
97d
4g
4h
96d
96
99
98
98
a Unless otherwise specified, the reaction was carried out in the presence
of 20 mol % catalyst. b Isolated yield. c Determined by HPLC (see Sup-
porting Information). d The result was reported in ref 9. e In the presence
of 2 mol % catalyst. f The reaction was performed at 0 °C. g The reaction
was performed at -25 °C.
>99d
>99d
99d
i-Pr
c-C6H11
8-13). These results confirm that the electron-nature of the
substituent bonded to either the R- or â-carbon of organocata-
lysts 4 is crucial to the catalytic performance. Comparison of
results observed with 4d, 4g, 4j, and 4m indicated that the (R)-
configuration13 of R- and â-carbons of catalysts with the ester
group matched the L-proline to enhance the stereochemical
control.
a The reaction was carried out in neat acetone with a concentration of
0.5 M at -25 °C for 24-48 h (see Supporting Information). b Isolated yields.
c Determined by HPLC. d In the presence of 5 mol % 4g.
Table 4. Direct Aldol Reactions of Aldehydes with Butanonea
Further optimization of the reaction conditions for the best
catalyst 4g revealed that the enantioselectivity increases sig-
nificantly to 99% ee with a decrease in the reaction temperature
to -25 °C (entry 15). Interestingly, as little as 2 mol % of 4g
is enough to promote the reaction with high conversion and
enantioselectivity (entries 14 and 15).
product
yield
(%)b
ee
product
yield
(%)b
dre
eec
(%)
entry
R
15
(%)c
16
anti/syn
1
2
3
NO2
Cl
CN
15a
15b
15c
56
43
62
98
98
>99
16a
16b
16c
42
>99:1
>99:1
>99:1
99
98
99
36
21d
Scope and Limitation. The scope and limitations of the direct
Aldol reaction catalyzed by 4g were also examined. A wide
range of aldehydes including both aromatic and aliphatic
aldehydes react smoothly with acetone under optimal conditions,
to give the Aldol adducts with excellent enantioselectivities
ranging from 96% to >99% ee (Table 3). Significantly, the
reactions of aromatic aldehydes bearing either an electron-
withdrawing or electron-donating group with acetone lead to
the formation of Aldol products 5a-5m with very high
enantioselectivities ranging from 96% to 99% ee (entries 1-13).
However, the previously developed organocatalyst 4f provides
excellent enantioselectivity (up to 93% ee) only for special
aromatic aldehydes with electron-withdrawing substituents.9
Remarkably, the benzaldehydes substituted with an electron-
donating group such as p-methylbenzaldehyde and p-tert-
butylbenzaldehyde also react smoothly with acetone to generate
Aldol adducts 5h and 5i with respective ee values of 97% and
96% (entries 8 and 9). Extremely high enantioselectivities g99%
ee are also observed for R-branched aliphatic aldehydes (entries
14-16). Particularly, an improved enantioselectivity of 99%
ee for cyclohexylformaldehyde (entry 16) was observed with
4g relative to its analogue 4f.9
a The reaction was carried out in neat butanone with a concentration of
0.5 M at -25 °C for 24-48 h. b Isolated yields. c Determined by HPLC.
d In the presence of 5 mol % 4g. e Determined by analysis of 1H NMR
spectra of the crude products.
15 in the majority and 16 in the minority. Although the
regioselectivity is not significant (up to 3/1), remarkably high
enantioselectivities of up to >99% ee are provided with 4g for
the major products 15a-c generated from reactions of 4-ni-
trobenzaldehyde, 4-chlorobenzaldehyde, and 4-cyanobenzalde-
hyde with 2-butanone. It is noteworthy that the minor Aldol
adducts 16a-c were obtained with extremely high diastereo-
selectivities of over 99:1 in favor of anti-diastereomers. Enan-
tioselectivities of 98-99% ees were observed for the anti Aldol
adducts 16a-c.
Cyclohexanone and cyclopentanone were finally explored as
Aldol donors. Cyclohexanone reacted with p-nitrobenzaldehyde
to generate Aldol adduct 17a in a high yield. The diasteomeric
1
ratio of anti/syn is 95/5 according to H NMR analysis of the
crude product, which is much higher than those observed with
the organocatalysts reported previously.5d,10b However, lower
enantioselectivity of 79% relative to L-proline was induced for
the anti-product (eq 1). The reaction of cyclopentanone went
smoothly to give 18a in 85% yield. The diasteomeric ratio of
anti/syn is almost 1/1. High enantioselectivity of 93% ee was
observed for anti-18a, but syn-18a was produced with low
enantioselectivity (eq 2).
Reactions of butanone with various para-substituted aromatic
aldehydes were investigated (Table 4). The reaction preferen-
tially occurred at the methyl group to generate Aldol adducts
(13) Actually, 4g has the same relative configuration as 4f. The (R)-configuration
comes from the higher priority of the ester group based on the sequence
rule of the Cahn-Ingold-Prelog convention.
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Organocatalyst for Direct Aldol Reactions
A R T I C L E S
relative to that in TS1 might be formed because of the strong
electron-withdrawing nature of the ester groups, which is a
highly possible reason that organocatalyst 4g shows much higher
catalytic activity and enantioselectivity than 4f.
Conclusion
In summary, a family of L-proline amides derived from
various chiral â-amino alcohols substituted with either electron-
donating or -withdrawing groups at their stereogenic centers
was evaluated for their ability to catalyze the direct Aldol
reaction of 4-nitrobenzaldehyde with acetone. We found that
catalysts with strongly electron-withdrawing groups show much
higher catalytic activity and enantioselectivity than their ana-
logues with electron-donating groups. The presence of 2 mol
% catalyst 4g significantly catalyzes the direct Aldol reactions
of a wide range of aldehydes with acetone and butanone, to
give the â-hydroxy ketones with very high enantioselectivities
ranging from 96% to >99% ee. The catalytic Aldol reaction of
cyclohexanone led to the formation of anti Aldol product in
high diastereoselectivity. Cyclopentanone reacted with 4-ni-
trobenzaldehyde to give excellent enantioselectivity for anti-
product. In addition to these results, our finding may provide
some insight for the further modification of related organocata-
lysts.
Transition State Consideration. The organocatalyst 4f
shows much better ability at controlling the stereochemical
outcome of the direct Aldol reaction than its structural analogues
4b, 4i, and 4l. 4f catalyzes the reaction via the transition state
TS1 (Figure 3), which was proposed previously on the basis of
the DFT calculation.9 Catalyst 4g, which has the same relative
configuration as 4f,13 also provides much higher enantioselec-
tivity than its diastereomers 4d, 4j, and 4m. Therefore, we
believe that the 4g catalyzed direct Aldol reaction via the
transition state TS2. The stronger double hydrogen bond in TS2
Acknowledgment. We are grateful for financial support from
National Natural Science Foundation of China (projects 20472082,
203900505 and 20325211). We also thank Professor Yun-Dong
Wu for his helpful discussion and suggestions.
Supporting Information Available: Experimental details and
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 3. Proposed transition states to account for the stereochemical
outcome.
JA0510156
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