Sterically and electronically tunable and bifunctional organocatalysts: Design and application in asymmetric aldol reaction of cyclic ketones with aldehydes

Article abstract of DOI:10.1021/jo0615089

Sterically and electronically tunable and bifunctional organocatalysts have been developed and evaluated in the direct aldol reaction of heterocyclic ketones. Catalysts with different substituents showed variable catalytic efficiency for analogous substra

Full text of DOI:10.1021/jo0615089

Sterically and Electronically Tunable and Bifunctional
Organocatalysts: Design and Application in Asymmetric Aldol
Reaction of Cyclic Ketones with Aldehydes
Jia-Rong Chen, Xin-Yong Li, Xiao-Ning Xing, and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal UniVersity, 152 Luoyu Road, Wuhan, Hubei 430079, China
wxiao@mail.ccnu.edu.cn
ReceiVed July 20, 2006
Sterically and electronically tunable and bifunctional organocatalysts have been developed and evaluated
in the direct aldol reaction of heterocyclic ketones. Catalysts with different substituents showed variable
catalytic efficiency for analogous substrates, indicating the importance of fine-tuning the strength of the
hydrogen bonding in the two NH groups. The reactions all proceeded in good to high yield and with
excellent enantioselectivities ranging from 90% to >99% ee. In most cases, high diastereoselectivities
ranging from 96/4 to 99/1 were obtained for the anti aldol adduct.
Introduction
silyl enol ether, methyl enol ethers, or ketone silyl acetals is a
necessity. Moreover, biochemical catalysis also has limitations
with regard to the scope and catalyst preparation. Thus, the
The aldol reaction is recognized as one of the most powerful
methods for the construction of new carbon-carbon bonds in
organic synthesis. During the carbon-carbon bond forming
process, the control of both the absolute and the relative
configuration of the aldol products is of paramount importance
for the synthesis of natural products.1 Since the pioneering work
of Mukaiyama et al.,2a considerable attention has been directed
toward the development of catalytic systems for asymmetric
aldol reactions.3,4 A great number of different approaches have
been made in this regard, including chiral Lewis acid-catalyzed
Mukaiyama reactions of silyl enol ethers,2b catalysis by Lewis
bases,5 and application of aldolases or antibodies.6 While
catalytic activation of aldehyde acceptors by chiral Lewis acids
has achieved success for the asymmetric aldol condensation,
preconversion of the donors to more reactive species such as a
(3) 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)
Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (f) 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.
(4) For examples of metal-mediated direct aldol reactions, see: (a)
Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem.
1997, 109, 1290; Angew. Chem., Int. Ed. 1997, 36, 1871. (b) Trost, B. M.;
Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (c) Yoshikawa, N.; Kumagai,
N.; Matsunaga, S.; Moll, G.; Oshima, T.; Suzuki, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2466. (d) Kumagai, N.; Matsunaga, S.; Yoshikawa,
N.; Oshima, T.; Shibasaki, M. Org. Lett. 2001, 3, 1539. (e) Trost, B. M.;
Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497. (f) Evans, D. A.; Tedrow,
J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392.
(5) (a) Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J. Am. Chem.
Soc. 1997, 119, 2333. (b) Denmark, S. E.; Stavenger, R. A. Acc. Chem.
Res. 2000, 33, 432. (c) Denmark, S. E.; Pham, S. M.; Stavenger, R. A.; Su,
X.; Wong, K.-T.; Nishigaichi, Y. J. Org. Chem. 2006, 71, 3904.
(6) Machajewski, T. D.; Wong, C.-H. Angew. Chem. 2000, 112, 1406;
Angew. Chem., Int. Ed. 2000, 39, 1352.
(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.
(2) (a) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. Chem Lett. 1990,
1455. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503.
10.1021/jo0615089 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/15/2006
8198
J. Org. Chem. 2006, 71, 8198-8202

Tunable and Bifunctional Organocatalysts
SCHEME 1. Highly Enantioselective Direct Aldol Reaction
Catalyzed by L-Proline or Its Derivatives and Analogues
FIGURE 1. Tunable and bifunctional organocatalysts and Gong’s
amino alcohol catalysts.
acetone, and some enolizable aldehydes are excellent nucleo-
philes, a variety of other donors, e.g., acetophenone, 3-pen-
tanone, and cyclic ketones did not yield a significant amount
of the desired aldol products with satisfactory selectivity.12a,13a
Recently, the highly diastereo- and enantioselective direct aldol
reaction between heterocyclic ketones and aldehydes was
reported by Pihko’s group, although the process was somewhat
sluggish.16 Recent studies by the groups of Barbas,17a Hayashi,17b
and Co´rdova17c revealed the enantioselective direct aldol reac-
tions of cyclohexanone in water, which open a new way for
the development of asymmetric organocatalysis in water.
However, the search for an efficient organocatalyst that shows
high diastereo- and enantioselectivities for a broad range of
cyclic ketone donors is still a problem waiting to be solved.
In our continuing efforts to develop readily tunable organo-
catalysts of broad utility for chemical transformations,15g we
combined the proline catalysis concept with hydrogen-bond
activation and designed a series of tunable bifunctional orga-
nocatalysts (1) (Figure 1). Initial studies revealed that catalyst
1b had the highest catalytic activity for the aldol reaction
between cyclohexanone and aldehydes. More importantly, we
demonstrated that an elegant alignment of the steric and
development of a direct catalytic asymmetric aldol reaction with
aldehydes and unmodified ketones is a noteworthy endeavor.7
A breakthrough in this strategy was realized by Shibasaki’s
success in developing heterobimetallic multifunctional catalyzed
direct asymmetric aldol reaction, although the enantioselectivi-
ties are currently modest.4a,8 Recently, Trost4b,9 and Evans10 and
co-workers demonstrated the highly enantioselective direct aldol
reaction catalyzed by zinc and nickel complexes. Almost three
decades after the first report of the intramolecular aldol reaction
catalyzed by L-proline,11 Barbas12a and List12b,c and co-workers
described the L-proline catalyzed intermolecular direct aldol
reaction using unmodified ketones as donors. Since then, there
has much research activity in this area, most of which has been
directed toward developing novel catalysts as well as extending
the substrate scope. Impressive results were obtained for various
kinds of aldehydes and R-ketoesters as acceptors when L-
proline12,13 or its derivatives and analogues14,15 were used
(Scheme 1).
Despite the substantial variety of aldol acceptors, the range
of donors has remained narrow. Whereas acetone, hydroxy
(7) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons: New York, 1994. (b) Sawamura, M.; Ito, Y. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 367-
388.
(8) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M.
J. Am. Chem. Soc. 1999, 121, 4168.
(9) Trost, B. M.; Ito, H.; Siloff, E. R. J. Am. Chem. Soc. 2001, 123,
3367.
(10) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706.
(11) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
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(12) (a) Sakthievel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem.
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Chem. Soc. 2000, 122, 2395. (c) Notz, W.; List, B. J. Am. Chem. Soc. 2000,
122, 7386.
(13) For selected reviews, see: (a) List, B. Synlett 2001, 1675. (b) List,
B. Tetrahedron 2002, 58, 5573. (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. (f) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. For selected
examples, see: (g) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798. (h) Co´rdova, A.; Notz, W.; Barbas, C. F., III. J.
Org. Chem. 2002, 67, 301. (i) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen,
K. A. Chem. Commun. 2002, 620. (j) Pidathala, C.; Hoang, L.; Vignola,
N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785. (k) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2004, 43, 2152. (l) Northrup, A. B.; MacMillan, D. W. C. Science 2004,
305, 1752. (m) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Co´rdova,
A. Angew. Chem., Int. Ed. 2005, 44, 1343. (n) Samanta, S.; Zhao, C.-G. J.
Am. Chem. Soc. 2006, 128, 7442. (o) Suri, J. T.; Mitsumori, S.; Albertshofer,
K.; Tanaka, F.; Barbas, C. F., III. J. Org. Chem. 2006, 71, 3822.
(14) (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245. (b)
Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167. (c)
Hartikaa, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831.
(d) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983. For review, see: (e) Saito, S.; Yamamoto,
H. Acc. Chem. Res. 2004, 37, 570.
(15) (a) Martin, H. J.; List, B. Synlett 2003, 1901. (b) Kofoed, J.; Nielsen,
J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445. (c) Tang, Z.;
Jiang, F.; Yu, L.-T.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J.
Am. Chem. Soc. 2003, 125, 5262. (d) 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. (e) Tang, Z.; Yang, Z.-H.; Chen, C.-H.; Cun, L.-F.; Mi,
A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285. (f)
Tang, Z.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org.
Lett. 2006, 8, 1263. (g) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan,
J.; Xiao, W.-J. Org. Lett. 2005, 7, 4543. (h) Berkessel, A.; Koch, B.; Lex,
J. AdV. Synth. Catal. 2004, 346, 1141. (i) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3,
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5321. (k) Ibrahem, I.; Co´rdova, A. Tetrahedron Lett. 2005, 46, 3363. (l)
Samanta, S.; Zhao, C.-G. Tetrahedron Lett. 2006, 47, 3383. (m) Jiang, M.;
Zhu, S.-F.; Yang, Y.; Gong, L.-Z.; Zhou, X.-H.; Zhou, Q.-L. Tetrahedron:
Asymmetry 2006, 17, 384. (n) Grondal, C.; Enders, D. Tetrahedron 2006,
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2006, 799.
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(17) (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734. (b) Hayashi, Y.;
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J. Org. Chem, Vol. 71, No. 21, 2006 8199

Chen et al.
TABLE 1. Enantioselective Direct Aldol Reaction of
p-Nitrobenzaldehyde 5a with Cyclohexanone 4 Catalyzed by
Catalyst 1a
carboxyl and the secondary amines were established to be
essential for good catalytic performance.19
In this context, we therefore designed a series of L-proline
derivatives which have two N-H groups as hydrogen bonding
donors, and the strength of acidity of N-H group can readily
be tuned by only changing the substitutent on the N atom (Figure
1). More importantly, compared with the synthetic route to
catalyst 3,15c,e all of our diamide catalysts can easily be obtained
in three steps from commercially available materials in good
overall yields.15g
yieldb
entry catalyst (%)
eed
yieldb
eed
drc (%) entry catalyst (%)
drc (%)
1
2
3
1a
1b
1c
73 84:16 54
81 75:25 86
89 76:24 80
4
1d
1e
1b
63 77:23 73
79 73:27 73
81 98:2
Optimization of Reaction Conditions with the Use of
Tunable and Bifunctional Organocatalysts 1 and 2. We
previously developed highly enantioselective direct aldol reac-
tions between cyclohexanone and aldehydes by using the
bifunctional organocatalyst 1d (Table 1). As an extension of
our current strategy, we first screened the ability of this type of
organocatalyst for the direct aldol reactions with heterocyclic
ketones 7-9 and aldehyde acceptor 5a. As summarized in Table
2, in the case of 1-Boc-4-piperidone 7, catalyst 1c shows the
highest efficiency while catalyst 2 is the best choice for
tetrahydro-4H-pyran-4-one 8 and tetrahydro-4H-thiopyran-4-one
9 (Table 2, entries 1-6). Comparing these results with previous
studies revealed that 1d had the highest activity for the
aldolization of cyclohexanone. In this respect, fine-tuning the
catalytic properties of organocatalyst 1 or 2 is very important
to the asymmetric induction. Further reaction optimization,
which included examination of solvents, temperature, and
additives for the superior catalysts 1d and 2, revealed that as
high as 99% ee and 99:1 dr can be obtained at -40 °C (Table
2, entry 13).
5
6e
97
a The reactions were conducted with 1 (20 mol %), AcOH (20 mol %),
5a (0.5 mmol), and 4/CHCl3 (1:1) (2 mL) for 6-24 h. b Isolated yields.
c Determined by 1H NMR spectroscopy. d Determined by chiral-phase HPLC
analysis for the anti-product. e Reaction performed at -40 °C.
SCHEME 2. Highly Enantioselective Direct Aldol Reaction
of Cylclic Ketones with Aldehydes
Catalyst Survey. A. Aldolization of Cyclic Ketone 7 with
Aldehyde. After establishing the optimal reaction conditions
for ketone 7, the direct asymmetric aldol reactions of other
aldehyde acceptors were carried out (Table 3). Aromatic,
heteroaromatic, and aliphatic adehydes were found to be suitable
substrates, with the direct aldol reactions generally giving the
corresponding aldol adducts in moderate to good yields. The
only exception to the generally high diastereo- and enantio-
selectivities was 2-thienaldehyde 5l, although the dr was still
high at 91:9 (Table 3, entry 12). Excellent diastereo- and
enantioselectivities were observed in most cases (>96:4 dr;
>94% ee). For instance, the reaction worked extremely well
with an R-branched aliphatic aldehyde to generate nearly
optically pure aldol adducts (97:3 dr; 98% ee) (Table 3, entry
13). Although the addition of a small amount of water often
accelerates reactions and/or improves enantioselectivities,14d the
positive effect of water was not observed for ketone 7 (Table
3, entries 2 versus 3).17
electronic properties of the catalyst is essential to maximize the
reaction efficiency (Table 1).
Significantly, the absolute configuration of major aldol adduct
6 was determined to be (2R,1′S) by comparison of the HPLC
retention time of the product with reported data.15e,17 The
improvement in enantioselectivity of catalyst 1 and the complete
difference in the configuration of the anti product suggests that
there is an inherent difference between L-proline and catalyst
1. On the basis of the success of the initial study, we then
examined the use of catalyst 1 for a broad range of cyclic
ketones. We now present the development of the readily tunable
diamide as a general catalyst for the direct asymmetric aldol
reaction between cyclic ketones and aldehydes, with unprec-
edented high efficiency in terms of reactivity and diastereo- and
enantioselectivity (Scheme 2).
B. Aldol Reaction of Tetrahydro-4H-pyran-4-one 8 with
Aldehydes. We then examined the ability of diamide catalyst
2 to catalyze the enantioselective direct aldol reaction of ketone
8 and various aldehydes. As illustrated in Table 4, both aromatic
and heteroaromatic aldehydes react smoothly with 8 under
optimal conditions to yield the aldol products in excellent
selectivities (>95:5 dr, >97% ee). Both para-substituted alde-
hydes 5a and 5k proved to react with a similar level of efficiency
as 5j (Table 4, entries 1, 11, and 10), showing little dependence
of the reaction on the electronic character of the aldol acceptor.
Significantly, high reactivity and selectivity were also observed
for heteroaromatic aldehydes 5l and 5m with dr and ee values
of >99:1 and > 99%, respectively (Table 4, entries 12 and 13).
Results and Discussions
Catalyst Design.According to the Houk-List model,18 the
high catalytic efficiency of proline is ascribed to the dual
activation of both the electrophilic aldehyde and the nucleophilic
aldol donor. This means that the carboxylic acid functionality
of proline controls the approach of the electrophile to the
enamine intermediate by hydrogen bonding. However, fine-
tuning of the catalytic properties of proline by derivatization is
difficult: the five-membered pyrrolidine ring as well as the
(18) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911.
(b) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc.
2003, 125, 16. (c) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J.
Am. Chem. Soc. 2003, 125, 2475. (d) Clemente, F. R.; Houk, K. N. J. Am.
Chem. Soc. 2005, 127, 11294.
(19) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904.
8200 J. Org. Chem., Vol. 71, No. 21, 2006

Tunable and Bifunctional Organocatalysts
TABLE 2. Optimization of Conditions for the Direct Aldol Reactions of Heterocyclic Ketones with p-Nitrobenzaldehydea
10a
11a
12a
entry
cat
solvent
yieldb (%)
drc
eeb (%)
yieldb (%)
drc
eeb (%)
yieldb (%)
drc
eeb (%)
1
1a
1b
1c
1d
1e
2
1d
1d
1d
1d
1d
1d
2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
toluene
CH3CN
DMF
79
81
92
85
83
94
85
93
90
98
89
89
76:24
78:22
81:19
92:18
81:19
81:19
79:21
87:13
81:19
81:19
90:10
96:4
77
80
86
87
80
75
82
89
82
87
92
94f
82
85
93
78
80
82
92
87
95
93
92
72
91
69:31
61:39
71:29
73:27
69:31
85:15
83:17
93:7
83:17
80:20
94:6
92:8
99:1
52
69
78
92
72
91
83
72
83
46
19
83
88
91
83:17
85:15
87:13
96:4
70
2
42
68
3
66
74
4
64
54
5
62
85:15
90:10
87:13
93:7
56
6
78
70
7
71e
87e
69e
67e
90e
96e,g
99g,h
74e
88e
82e
82e
86e
98e,f
99f,h
8
9
93:7
10
11
12
13
94:6
THF
94:6
THF
THF
99:1
99:1
a The reactions were conducted with catalyst (20 mol %), AcOH (40 mol %), p-nitrobenzaldehyde (0.5 mmol), ketone (2.5 mmol), and THF (2 mL).
b Isolated yields. c Determined by 1H NMR spectroscopy. d Determined by chiral-phase HPLC analysis for the anti-product. e Catalyst 2 was used. f Reaction
performed at -20 °C. g Reaction performed at -40 °C. h 10 equiv H2O was added.
TABLE 3. Scope of the Direct Aldol Reaction of Aldehydes 5 with
Ketone 7a
TABLE 4. Scope of the Direct Aldol Reaction of Aldehydes 5 with
Ketone 8a
entry
R
product
yieldb (%)
drc
eed (%)
entry
R
product
yieldb (%)
drc
eed (%)
1
4-NO2-Ph-
3-NO2-Ph-
2-NO2-Ph-
4-CN-Ph-
4-Br-Ph-
3-Br-Ph
4-Cl-Ph-
2-Cl-Ph-
4-F-Ph-
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
91
96
94
81
89
81
70
77
85
80
77
89
67
55
>99:1
97:3
99
>99
>99
99
>99
99
1
4-NO2-Ph-
4-NO2-Ph-
4-NO2-Ph-
3-NO2-Ph-
2-NO2-Ph-
4-Br-Ph-
3-Br-Ph-
4-Cl-Ph-
2-Cl-Ph-
4-F-Ph
10a
10a
10a
10b
10c
10d
10e
10f
10g
10h
10i
89
86
90
91
80
86
80
80
70
75
80
32
58
96:4
98:2
96:4
96:4
96:4
97:3
99:1
97:3
97:3
98:2
96:4
91:9
97:3
94
98
96
93
92
95
96
95
94
94
90
86
98
2
2e
3f
4
3
99:1
4
97:3
5
95:5
5
6
99:1
6
7
>99:1
>99:1
99:1
>99
>99
>99
99
7
8
8
9
9
10
11
12
13
14
Ph-
99:1
10
11
12g
13
4-Me-Ph-
2-furyl-
2-thienyl
1-naphthyl
>99:1
>99:1
>99:1
>99:1
99
Ph-
>99
>99
98
2-thienyl
i-Pr
10j
10k
a The reactions were conducted with catalyst 1d (20 mol %), AcOH (40
mol %), aldehyde 5 (0.5 mmol), ketone 7 (2.5 mmol), and THF (2 mL) for
a Reactions were conducted with catalyst 2 (20 mol %), AcOH (40 mol
%), aldehyde 5 (0.5 mmol), ketone 8 (2.5 mmol), H2O (10 equiv based on
the aldehyde), and THF (2 mL) for 18-114 h. b Isolated yields. c Deter-
mined by 1H NMR spectroscopy. d Determined by chiral-phase HPLC
analysis for the anti-product.
1
41-96 h. b Isolated yields. c Determined by H NMR spectroscopy. d De-
termined by chiral-phase HPLC analysis for the anti-product. e Reaction
performed at -40 °C. f 10 equiv H2O was added at -40 °C. g Reaction
performed at 0 °C.
bearing electron-withdrawing groups with ketone 9 affords the
aldol adducts 12a-j in good to excellent yield, with enantio-
selectivities ranging from 97% to 99% ee (Table 5, entries
1-10). In general, the reactions of aromatic aldehydes with two
electron-withdrawing substituents are better with ketone 9 in
terms of both reactivity and selectivity (entries 7-9). By
contrast, the reaction of the aliphatic aldehyde 5m afforded
somewhat lower product yield, while the dr and ee values were
up to 98:2 and 99%, respectively.
A similar study was reported by Pihko’s research group using
L-proline as the catalyst.16 However, our reaction times are
generally shorter (24-120 h versus 72-216 h), our yields (55-
98% versus 40-76%), as well as dr (91/9-99/1 versus 4/ 1-20/
1) and ee values (90-99% versus 73-99%), are higher, and
most importantly our catalysts have greater substrate scope.
Note that the reactions of ketone 8 with various aldehydes were
performed in the presence of 10 equiv of water. It was observed
that the addition of water has a positive effect on the catalytic
performance of catalyst 2 in this case (Table 2, entries 12 versus
13).
C. Aldol Reaction of Tetrahydro-4H-thiopyran-4-one 9
with Aldehydes. Finally, we examined the use of tetrahydro-
4H-thiopyran-4-one 9 for the aldol-type process. Gratifying
results were obtained with this ketone, which gave very high
enantio- and diastereoselectivities using different kinds of
aldehydes. In the reaction of 5a with 9 (Table 5, entry 1), no
dehydration products were detected by 1H NMR analysis,
indicating 12a to be the sole product (99:1 dr; 99% ee). Other
results are listed in Table 5. The reactions of aromatic aldehydes
J. Org. Chem, Vol. 71, No. 21, 2006 8201

Chen et al.
TABLE 5. Scope of the Direct Aldol Reaction of Aldehydes 5 and
Ketone 9a
zaldehyde (5a) went smoothly to give 14 in 57% isolated yield
with 77% ee (eq 3).15g
Conclusion
In summary, we have demonstrated that the readily tunable
and bifunctional diamide catalysts 1d and 2 can catalyze the
direct aldol reactions of heterocyclic ketones with various
aldehydes, affording more than 30 different compounds in 94-
99% ee. We found that different catalyst analogues showed
variable catalytic activities for different aldol donors. Appropri-
ate catalysts can easily be obtained just by changing the
substitutents on the NH groups. In this regard, the design and
use of 1 and 2 raise the possibility of developing sterically and
electronically flexible novel catalysts that have high reactivities
for asymmetric organocatalysis. Significantly, our strategy
allows the use of 4-thianone, a surrogate for unreactive
3-pentanone, for the aldol reaction affording excellent diastereo-
and enantioselectivies. The latter has potential for the construc-
tion of polypropionate building blocks after removal of the sulfur
bridge.21 The amount of catalyst can be reduced to 2 mol %
without the loss of catalytic efficiency. Further studies about
the detailed role of the two NH groups in our catalysts, and
investigations of the capacity of these catalysts toward new
reactions, are currently underway in our laboratory.
entry
R
product
yieldb (%)
drc
eed (%)
1
4-NO2-Ph-
3-NO2-Ph-
2-NO2-Ph-
4-CN-Ph-
4-Br-Ph-
3-Br-Ph-
4-Cl-Ph-
2-Cl-Ph-
2,4-Cl2-Ph-
4-F-Ph-
12a
12b
12c
12d
12e
12f
12g
12h
12i
91
88
93
98
90
78
63
91
99
74
61
37
45
99:1
92:8
98:2
98:2
99:1
99:1
99:1
89:11
97:3
99:1
97:3
99:1
99:1
99
98
99
99
97
99
99
98
99
97
90
99
99
2
3
4
5
6
7
8
9
10
11
12
13
12j
12k
12l
Ph-
1-naphthyl
1-thienyl
12m
a Reactions were conducted with catalyst 2 (20 mol %), AcOH (40 mol
%), aldehyde 5 (0.5 mmol), ketone 8 (2.5 mmol), H2O (10 equiv based on
the aldehyde), and THF (2 mL) for 24-120 h. b Isolated yields. c Deter-
mined by 1H NMR spectroscopy. d Determined by chiral-phase HPLC
analysis for the anti-product.
Moreover, a preliminary study showed that the catalyst loading
could be reduced to as low as 2 mol % for ketone 8, and the
results were comparable with that using 20 mol % catalyst,
though slightly longer reaction time was needed (eq 1).20
Experimental Section
General procedure for the Aldol Reaction of Cycloketone
with Aldehyde.The organocatalyst, l-prolinamide derivatives22 (0.1
mmol), ketone (2.5 mmol), and AcOH (0.2 mmol) were stirred in
2 mL THF for 10 min at -20 °C. The corresponding aldehyde 5
(0.5 mmol) was added, and the mixture was stirred for 41-96 h.
The mixture was treated with 10 mL saturated ammonium chloride
solution and extracted with ethyl acetate. The organic layer was
dried (MgSO4), filtered, and concentrated to give pure aldol adduct
through flash column chromatography on silica gel (hexane/ethyl
acetate (3:1)).
In addition, we have examined the feasibility of using other
cyclic and acyclic ketones as aldol donors. In the case of
cyclopentanone, excellent ee (>99%) for syn-isomer was
obtained; however, the diastereomeric ratio of anti/syn was
almost 1/1 (eq 2). The reaction of acetone with para-nitroben-
Acknowledgment. We are grateful to the National Science
Foundation of China (200472021), the National Basic Research
Program of China (2004CCA00100), the program for new
century excellent talents in university (NCET-05-0672), and the
Hubei Province Science Found for Distinguished Young Scholar
(2004ABBC011), for support of this research. We thank Dr.
Joel F. Austin for fruitful discussions.
Supporting Information Available: Experimental details and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0615089
(20) equiv ketone was used.
(21) Nishide, K.; Shigeta, Y.; Obata, K.; Aksela, R. Tetrahedron 1996,
37, 2271.
(22) For the preparation of catalysts 1a-e and 2, please see: Li, X.-Y.;
Chen, J.-R.; Meng, X.; Xiao, W.-J. Acta Crystallogr. 2005, E61, o2730
and ref 15g.
8202 J. Org. Chem., Vol. 71, No. 21, 2006