Chiral primary-tertiary diamine catalysts derived from natural amino acids for syn-aldol reactions of hydroxy ketones

Full text of DOI:10.1021/jo802557p

imine-enamine isomerization.2e,5 In recent years, the application
of primary amino acid derivatives in organocatalysis has
received rapidly growing attention because of the increasing
recognition of their relationship to biogenesis,6 their rediscovered
effectiveness in aldol catalysis,7 and their unprecedented syn
stereoselectivity in some direct aldol reactions.3 In the latter
cases, primary amino acids conjugated with additional chiral
building blocks were proven to be promising catalysts.3d Simple
primary amino acid derivatives, such as chiral vicinal diamines,
remain much less explored, however, though they have been
applied as chiral ligands in asymmetric catalysis8 or used as
iminium-type organocatalysts previously.9 In only one case was
the primary-tertiary diamine-Brønsted acid conjugate exam-
ined for asymmetric catalysis of direct aldol reactions. Unfor-
tunately, poor yield and stereoselectivity were obtained.10b Here,
we report a class of primary diamine catalysts derived from
Chiral Primary-Tertiary Diamine Catalysts
Derived From Natural Amino Acids for syn-Aldol
Reactions of Hydroxy Ketones
Jiuyuan Li,† Sanzhong Luo,*,† and Jin-Pei Cheng*,†,‡
Beijing National Laboratory for Molecule Sciences
(BNLMS), Center for Chemical Biology, Institute of
Chemistry, Chinese Academy of Sciences,
Beijing, 100190 China, and Department of Chemistry and
State Key Laboratory of Elemental-Organic Chemistry,
Nankai UniVersity, Tianjin, 300071 China
luosz@iccas.ac.cn
ReceiVed NoVember 18, 2008
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Res. 2004, 37, 580–591. (b) Mukherjee, S.; Yang, J. W.; Hoffman, S.; List, B.
Chem. ReV. 2007, 107, 5471–5569. For selected examples of anti-aldol reactions,
see: (c) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2004, 43, 2152. (d) Casas, J.; Engqvist, M.; Ibrahem, I.;
Kaynak, B.; Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 1343. (e) Northrup,
A. B.; MacMillan, D. W. C. Science 2004, 305, 1752. (f) Co´rdova, A.; Zou,
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2005, 44, 3055. (h) Enders, D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44,
1210. (i) Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2005, 7,
1383. (j) Ibrahem, I.; Co´rdova, A. Tetrahedron Lett. 2005, 46, 3363. (k) Torii,
H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1983. (l) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi,
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(3) For examples of syn-aldol reactions of ketones, see: (a) Ramasastry,
S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129,
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2007, 129, 3074–3075. (c) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.;
Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2007, 46, 5572–5575. (d)
Xu, X.-Y.; Wang, Y.-Z.; Gong, L.-Z. Org. Lett. 2007, 9, 4247–4249. (e) Utsumi,
N.; Imai, M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas, C. F., III. Org. Lett.
2007, 9, 3445–3448. (f) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.;
Barbas, C. F., III. Org. Lett. 2008, 10, 1621–1624. (g) Luo, S.; Xu, H.; Zhang,
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Gong, L.-Z. AdV. Synth. Catal. 2008, 350, 1390–1396.
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Chem. ReV 2007, 107, 5471–5569. For selected examples, see ref 10 and: (b)
Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong,
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A series of primary-tertiary diamine catalysts were designed
and synthesized from primary natural amino acids. Applica-
tion of these new chiral catalysts in direct aldol reactions of
R-hydroxyketones showed very good catalytic activity (up
to 97% yield) and high syn selectivity (up to syn/ anti )
30:1, 99% ee).
The aldol reaction has long been recognized as a useful
strategy to construct various C-C bonds in organic synthesis.1
The past decade has witnessed the extraordinary success of chiral
amines, particularly chiral pyrrolidines, as efficient enamine-
based asymmetric direct aldol catalysts.2 In this context, the
identification of chiral primary amine catalysts represents one
of the recent prominent progresses. Barbas, Gong, and this group
have independently reported a number of chiral primary amine
catalysts that enabled syn-aldol reactions of ketones.3 Despite
these notable achievements, development of simple and new
catalysts for efficient syn-aldol reactions is still highly desired.2b
Natural amino acids provide a versatile chiral pool for
evolution of organocatalysts as evidenced by the rapid ac-
cumulation of various L-proline-based chiral pyrrolidine cata-
lysts.4 However, primary amino acids (the other 20 amino acids)
seem to be almost overlooked for this kind of catalysts, due
partially to the initial findings of their ineffectiveness in catalyst
screening processes and also to the assumed unfavorable
† Chinese Academy of Sciences.
‡ Nankai University.
(1) For reviews on direct aldol reactions, see: (a) Modern Aldol Additions;
Mahrwald, R., Eds.; Wiley-VCH: Weinheim, 2004. (b) Palomo, C.; Oiarbide,
M.; Garcia, J. M. Chem.sEur. J. 2002, 8, 36–44. (c) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352–1374.
10.1021/jo802557p CCC: $40.75
Published on Web 01/16/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1747–1750 1747

TABLE 1. Screening of Catalysts in Aldol Reaction of
Hydroxyacetone
SCHEME 1. Catalysts Examined in This Study
entrya amine
solvent
toluene
n-hexane
DMF
MeOH
NMP
neat
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
NMP-n-hexane
yieldb (%) syn/antic eed (%)
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1b
1b
1b
1a
1c
1d
1e
1f
90
94
34
16
41
82
81
66
71
82
48
55
83
55
52
97
9:1
8:1
8:1
10:1
10:1
4:1
7:1
6:1
6:1
7:1
3:1
4:1
12:1
2:3
1:1
2:1
83
81
94
94
96
86
94
85
89
91
90
91
natural amino acids to give highly efficient and enantioselective
syn-aldol reactions of R-hydroxyketones (Scheme 1).
Chiral primary vicinal diamines were easily synthesized
according to the typical procedure in the literature.9a,10b After
trial and error, we were delighted to find that the simple
diamine-Brønsted acid conjugate could promote the direct aldol
reaction of R-hydroxyketone. As is well-known, aldol reaction
of hydroxyacetone is a versatile route to construct the 1,2-diol
building blocks for the synthesis of various natural and
biological active molecules.11 In this work, we selected the aldol
reaction of hydroxyacetone and p-nitrobenzaldehyde as a model
reaction to evaluate the diamine catalysts. Interestingly, syn
diastereoselectivity was observed in the catalysis of 1b·TfOH,
9
10
11
12
13
14
15
16
1g
1h
1i
93
76/62e
46/76e
25
1j
a Unless otherwise stated, 0.25 mmol of aldehyde with 0.5 mmol of
hydroxyacetone in 0.2 mL of solvent. b Isolated yield. c Determined by
1H NMR. d Determined by HPLC. e ee for anti product.
(7) For selected primary amino acid catalyzed direct aldol reactions, see: (a)
Sakathivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001,
123, 5260–5267. (b) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Co´rdova, A.
Angew. Chem., Int. Ed. 2005, 44, 7028–7032. (c) Co´rdova, A.; Zou, W.; Ibrahem,
I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem. Commun. 2005, 3586–3588.
(d) Co´rdova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Dziedzic, P Chem.sEur. J.
2006, 12, 5383–5397. (e) Deng, D.-S.; Cai, J. HelV. Chim. Acta 2007, 90, 114–
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Co´rdova, A Org. Biomol. Chem. 2006, 4, 38–40. (k) Zou, W.; Ibrahem, I.;
Dziedzic, P.; Sunde´n, H.; Co´rdova, A. Chem. Commun. 2005, 4946–4948. (l)
Tsogoeva, S. B.; Wei, S. Tetrahedron: Asymmetry 2005, 16, 1947–1951. (m)
Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.;
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Z.; Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007, 349, 812–816. (o) Jiang, Z.;
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20, 379–381.
and the related reactions were found to be highly solvent-
dependent. In nonpolar solvents such as n-hexane and toluene,
the reactions proceeded quite smoothly, giving high product
yield but moderate enantioselectivity (Table 1, entries 1 and
2). In polar solvents such as DMF, NMP, and methanol, though
the reactions were much slower than those in less polar solvents,
higher enantioselectivity was observed (Table 1, entries 3-5).
Further examination indicated that a mixed solvent such as
NMP-n-hexane (1:1, v/v) gave optimal results in terms of both
the yield and selectivity (Table 1, entry 7). Consequently,
NMP-hexane (1:1, v/v) was selected for subsequent optimiza-
tion. Other acidic additives were also examined, and TfOH was
found to give optimal results.
The reactions were further optimized using different chiral
amines. As shown in Table 1, the primary-tertiary diamine
catalysts 1a-d (derived from either L-phenylalanine or L-valine)
all worked well under the present conditions, among which 1b
gave the optimal results (Table 1, entry 7). Other primary amine
catalysts such as primary-secondary diamines 1e and 1f, amino
alcohol 1j, and the amide-type catalysts 1h and 1i have also
been tested in the present reaction. They generally exhibited
inferior selectivity and activity (Table 1, entries 11-15). These
results highlighted the importance of the primary-tertiary
diamine skeleton for effective aldol catalysis. Under the optimal
conditions, the reaction catalyzed by 1b·TfOH gave 81% yield,
7:1 syn/anti, and 94% ee, which is comparable to those of the
reaction with 1g·TfOH (Table 1, entry 13).
(9) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504–10505.
(b) Ishihara, K.; Nakano, K.; Akakura, M. Org. Lett. 2008, 10, 2893–2896. (c)
Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930–8931.
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Tetrahedron 2002, 58, 8167–8177. (c) Ishii, T.; Fujioka, S.; Sekiguchi, Y.;
Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558–9559. (d) Mase, N.; Watanabe,
K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 4966–4967. (e) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734–735. (f)
Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624–9625. (g) Gryko,
D.; Zimnicka, M.; Lipin´ski, R. J. Org. Chem. 2007, 72, 964–970. (h) Luo, S.;
Xu, H.; Li, J.; Zhang, L.; Mi, X.; Zheng, X.; Cheng, J.-P. Tetrahedron 2007,
63, 11307–11314. (i) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2004, 43, 2420–2423. (j) Peng, F.-Z.; Shao, Z.-H.; Pu, X.-W.; Zhang,
H.-B. AdV. Synth. Catal. 2008, 350, 2199–2204.
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Synthesis II; Wiley-VCH: Weinheim, Germany, 2003; and references cited
therein. For efforts to construct 1,2-diols, see ref 3 and: (b) Yoshikawa, N.;
Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M.
J. Am. Chem. Soc. 2001, 123, 2466–2467. (c) Kumagai, N.; Matsunaga, S.;
Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 2169–2178. (d) Trost, B. M.; Ito, H.; Silcoff,
E. R. J. Am. Chem. Soc. 2001, 123, 3367–3368. (e) Shabat, D.; List, B.; Lerner,
R. A.; Barbas, C. F., III. Tetrahedron Lett. 1999, 40, 1437–1440. (f) List, B.;
Shabat, D.; Barbas, C. F., III; Lerner, R. A. Chem. Eur. J. 1999, 4, 881–885. (g)
Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570–
7571. (h) Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc.
1994, 116, 1278–1291. (i) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122,
7386–7387.
The application of catalyst 1b·TfOH in the aldol reaction of
hydroxyacetone was next examined. The reaction worked well
with aromatic aldehydes bearing either electron-withdrawing or
electron-donating groups to give highly syn-selective aldol
adducts and good enantioselectivity (91-97% ee) at room
temperature. Slightly higher diastereoselectivity was generally
observed with ortho-substituted aromatic aldehydes (Table 2,
entries 3 and 7). Notably, aliphatic aldehydes were also applied
in the present reactions offering syn-selective aldol adducts with
high enantioselectivity. For example, the reaction of cyclohex-
1748 J. Org. Chem. Vol. 74, No. 4, 2009

TABLE 2. 1b·TfOH-Catalyzed Aldol Reaction of Hydroxyacetone
TABLE 3. Screening of Catalysts in the Aldol Reaction of DHA
time
(h)
yieldb
(%)
syn/
antic
eed
(%)
entrya
amine
acid
TfOH
yieldb (%)
syn/antic
eed (%)
entrya
R
1
2
3
1b
1b
1b
1b
1b
1b
1a
1c
1d
1g
94
57
97
92
82
78
83
94
87
95
30:1
24:1
30:1
19:1
24:1
13:1
19:1
16:1
16:1
24:1
99
98
99
98
95
95
96
92
93
27
1
2
3
4
5
6
7
8
9
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CF3Ph
4-CNPh
4-ClPh
24
48
48
48
48
72
72
72
48
48
2a/81
2b/94
2c/87
2d/97
2e/92
2f/78
2g/82
2h/54
2i/56
2j/55
7:1
6:1
10:1
8:1
6:1
8:1
94
94
96
93
93
91
95
93
93
80
TFA
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
4e
5e
6e
7
2-BrPh
cyclohexane
10:1
7:1
8
9
10
2-phenylpropanal
2, 2′-dimethoxyacetaldehyde
10:1e
3:1
10
a Unless otherwise stated, 0.25 mmol of aldehyde with 0.5 mmol of
hydroxyacetone in 0.2 mL of solvent. b Isolated yield. c Determined by
1H NMR. d Determined by HPLC. e For -Me, dr ) 3.5:1.
a Unless otherwise stated, 0.25 mmol of aldehyde with 0.5 mmol of
dihydroxyacetone in 0.2 mL of NMP, 6.67 mol % of H3PW12O40 was
used in entries 3-10. b Isolated yield. c Determined by HPLC.
d Determined by HPLC. e Second, third, and fourth reuse.
anecarbaldehyde gave the desired product with 7:1 syn/anti, 93%
ee, and 54% yield (Table 2, entry 9).
TABLE 4. 1b-POM Hybrid Catalyzed Aldol Reaction of DHA
In light of the above results, we further examined one other
important R-functionalized ketone, dihydroxyacetone (DHA).
DHA and its derivatives are versatile building blocks in the
chemical and enzymatic synthesis of carbohydrate.12 Though
DHA derivatives as aldol donors have been achieved via
organocatalysis,13 direct aldol reaction of free DHA remained
entrya
R
time (h)
yieldb (%)
syn/antic
eed (%)
1
2
3
4
5
6
7
8
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CF3Ph
4-CNPh
4-ClPh
24
24
24
36
36
72
72
72
3a/95
3b/90
3c/97
3d/92
3e/86
3f/59
3g/86
3h/61
30:1
13:1
30:1
24:1
16:1
8:1
95
94
99
96
91
91
84
95
unsolved until Barbas’s finding that primary amino acid could
3c,e,14
catalyze the syn-aldol reaction of DHA.
To our delight,
we found that 1b·TfOH could also catalyze the aldol reaction
of DHA in NMP with high yield and selectivity (Table 3, entry
1). Other acidic additives were also examined, and the use of
polyoxometalate H3PW12O40, a promising solid acid support for
chiral amine catalysts,15 provided the best results in terms of
both the yield and selectivity (Table 3, entry 3). Significantly,
the 1b-POM hybrid catalyst can precipitate out from the
reaction mixture and be easily recycled.15 The recovered catalyst
could be reused up to four times while maintaining high
enantioselectivity with a decrease of product yield in the third
and fourth run (Table 3, entries 4-6). The reactions using other
primary-tertiary diamine catalysts including diamine 1g de-
veloped earlier from this laboratory3b gave inferior results under
the present conditions (Table 3, entries 7-10).
3-BrPh
1-Naph
19:1
24:1
a Unless otherwise stated, 0.25 mmol of aldehyde with 0.5 mmol of
dihydroxyacetone in 0.2 mL of NMP. b Isolated yield. c Determined by
HPLC. d Determined by HPLC.
With the identified catalyst 1b, we next explored the scope
of aldol reaction of DHA. As shown in Table 4, the reaction
could be applied to a range of aromatic aldehydes to afford
mainly the syn selective aldol adducts with high yields and
excellent enantioselectivities at room temperature (Table 4).
Unfortunately, the reaction with aliphatic aldehydes gave poor
results due likely to the self-condensation reactions.
Other linear ketones, such as acetone, butanone, and benzy-
loxyacetone, were also tested with the optimal catalyst
1b·TfOH. While both acetone and butanone provided only poor
selectivity, the reaction of benzyloxyacetone exhibited high syn
selectivity with up to 98% ee (Scheme 2).
The absolute configurations of the syn-aldol products were
determined by comparison of the optical rotation value and
HPLC traces with the known compounds.3g Consistent with
previous reports, the high syn selectivity could be explained
by a Z-enamine transition state (Scheme 3).3b,4a In this model,
the N-H· · ·O hydrogen bond was assumed to play a critical
role for stabilizing the Z-enamine, consequently leading to high
syn selectivity.3a The observed lower selectivity with acetone
and butanone, wherein the intramolecular N-H· · ·O hydrogen
bonds are absent, is clearly in line with this hypothesis.
In conclusion, we have developed a class of primary-tertiary
diamine catalysts derived from natural amino acids that work
effectively with R-hydroxyketones as syn-selective aldol cata-
(12) For reviews, see: (a) Enders, D.; Voith, M.; Lenzen, A. Angew. Chem.,
Int. Ed. 2005, 44, 1304–1325. (b) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong,
C.-H. Chem. ReV. 1996, 96, 443–473.
(13) For selected aldol reactions of protected DHA, see: (a) Enders, D.;
Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210–1212. (b) Suri, J. T.;
Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2005, 7, 1383–1385. (c)
Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077–4079. (d)
Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2005,
44, 4079–4083. (e) Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.;
Barbas, C. F., III. J. Org. Chem. 2006, 71, 3822–3828. (f) Co´rdova, A.; Zou,
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5397. (g) Ibrahem, I.; Zou, W.; Xu, Y.; Co´rdova, A. AdV. Synth. Catal. 2006,
348, 211–222. (h) Grondal, C.; Enders, D. AdV. Catal. Synth. 2007, 349, 694–
702. For other organocatalytic de novo syntheses of sugars, see: (k) Chowdar,
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A. Angew. Chem., Int. Ed. 2005, 44, 1343–1345.
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J. Org. Chem. Vol. 74, No. 4, 2009 1749

SCHEME 2. 1b-Catalyzed Aldol Reaction of Linear
Aliphatic Ketones
nm, 2-propanol/n-hexane ) 1:4 as eluent, 25 °C, 0.8 mL/min), tR
) 12.74 min (minor syn isomer), tR ) 16.72 min (major syn
isomer), 94% ee (absolutely configuration: 3R,4S). Aldol products
2a-h3a,d,g and 4-6
have been reported; 2i,j were new
3g,2m,t
compounds, and their detailed characterization data are provided
in the Supporting Information.
Procedure for the Aldol Reaction of Free DHA. To 0.2 mL
of NMP were added 1b (8.2 mg, 0.050 mmol) and H3PW12O40 (48
mg, 0.0167 mmol). After the mixture was stirred for 10 min, DHA
(45 mg, 0.5 mmol) and 2-nitrobenzaldehyde (0.25 mmol) were
added. The homogeneous mixture was stirred for 24 h at room
temperature. Ethyl ether was then added to precipitate the catalyst.
The catalyst was washed three times with ethyl ether and then
directly used for the next run. The combined organics were
concentrated and purified by flash chromatography carefully to
afford 3c and then peracetylated with pyridine/Ac2O to afford 89
mg of colorless product. Yield: 97%.161H NMR (300 MHz, CDCl3):
δ 1.97 (3 H, s), 2.07 (3 H, s), 2.12 (3 H, s), 4.78-4.93 (2 H, m),
5.85 (1 H, d), 6.87 (1 H, d), 7.44-7.46 (1 H, m), 7.48-7.60 (2 H,
m), 8.03-8.06 (1 H, d). 13C NMR (75 MHz, CDCl3): δ 20.2, 20.3,
20.6, 66.4, 69.5, 76.4, 125.2, 128.9, 129.5, 131.9, 133.5, 147.4,
169.2, 169.9, 196.8. The enantiomeric excess was determined by
HPLC (AD-H column, 254 nm, 2-propanol/n-hexane ) 1:9 as
eluent, 0.8 mL/min) with free aldol adduct, tR ) 32.59 (major anti
isomer), tR ) 36.23 (minor anti isomer), tR ) 38.89 (major syn
isomer), tR ) 44.78 (minor syn isomer), 99% ee (absolutely
configuration: 3R,4S). Free aldol adducts 3a-h have been reported
by our group,3g peracetylated 3a-e,g,h were known compounds,3c,i
and peracetylated 3f was a new compound.
SCHEME 3. Transition State of syn-Aldol Reaction
lysts. Simple primary-tertiary diamine-Brønsted acids conju-
gates 1b·TfOH and 1b-POM were found to be the optimal
catalysts that render syn-aldol reactions of hydroxyketone with
up to 97% yield, 30:1 syn/anti, and 99% ee. Taking advantage
of biphasic properties of POM (H3PW12O40), the 1b-POM
hybrid catalyst can be easily recycled and reused four times.
Acknowledgment. This project was supported by the Natural
Science Foundation of China (NSFC 20421202, 20632060, and
20542007), the Ministry of Science and Technology (MoST),
and the Chinese Academy of Sciences.
Experimental Section
Procedure for the Aldol Reaction of Hydroxyacetone. Catalyst
1b·TfOH (8.9 mg, 0.025 mmol), hydroxyacetone (37 mg, 0.5
mmol), and 4-nitrobenzaldehyde (0.25 mmol) were mixed together
in 0.2 mL of n-hexane-NMP (1:1, v/v) at room temperature. The
mixture was stirred for 24 h and directly purified by flash
chromatography carefully to afford the aldol adducts 2a (46 mg)
Supporting Information Available: Synthesis of catalysts,
general experimental procedures, characterization data, and
NMR spectra for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
as white solid. Yield: 81%. H NMR (300 MHz, CDCl3): δ 2.36
JO802557P
(3 H, s), 2.69 (1 H, d), 3.70 (1 H, d), 4.41 (1 H, d), 5.20 (1 H, d),
7.60-7.63 (2 H, d), 8.23-8.26 (2 H, d). 13C NMR (75 MHz,
CDCl3): δ 26.0, 73.0, 80.0, 123.8, 127.2, 147.3, 157.8, 208.3. The
enantiomeric excess was determined by HPLC (AD-H column, 254
(16) In many cases, the free DHA is difficult to separate completely from
the products.
1750 J. Org. Chem. Vol. 74, No. 4, 2009