Highly efficient threonine-derived organocatalysts for direct asymmetrie aldol reactions in water

Article abstract of DOI:10.1002/adsc.200600564

The introduction of siloxy groups at the hydroxy function of natural threonine resulted in efficient hydrophobic organocatalysts, which could efficiently catalyze the direct aldol reactions of both cyclic and acyclic ketones with aromatic aldehydes in wat

Full text of DOI:10.1002/adsc.200600564

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DOI: 10.1002/adsc.200600564
Highly Efficient Threonine-Derived Organocatalysts for Direct
Asymmetric Aldol Reactions in Water
Xiaoyu Wu,a,d Zhaoqin Jiang,a,b,d Han-Ming Shen,c and Yixin Lua,b,*
a
Department ofChemistry, National University ofSingapore, 3 Science Drive 3, Singapore, 117543, Republic ofSingapore
Fax : (+65)-6779-1691; e-mail: chmlyx@nus.edu.sg
The Medicinal Chemistry Program, Office of Life Sciences, National University of Singapore, Republic of Singapore
Department ofCommunity, Occupational and Family Medicine, National University ofSingapore, Republic ofSingapore
X. W. and Z. J. made equal contributions to this work
b
c
d
Received: October 29, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The introduction ofsiloxy groups at the
hydroxy function of natural threonine resulted in
efficient hydrophobic organocatalysts, which could
efficiently catalyze the direct aldol reactions of both
cyclic and acyclic ketones with aromatic aldehydes
in water with excellent enantiomeric excess.
moted direct aldol reactions between cyclic ketones
and aromatic aldehydes in water.[10] In this communi-
cation, we disclose our findings that simple natural
threonine derivatives are excellent organocatalysts for
the direct aldol reactions in aqua.
For the design ofnovel catalysts, we are particularly
interested in the organocatalysts that can be easily de-
rived from the chiral pool. We hypothesized that in-
corporation ofa hydrophobic group into a natural
amino acid could generate a hydrophobic organocata-
lyst, which may interact favorably with organic sub-
strates in aqueous media due to its hydrophobic
nature.[11] With the properly designed catalysts, water
can be sequestered from the transition state and high
Keywords: aldol reaction; asymmetric catalysis; hy-
drophobic effect; organic catalysis; water
The asymmetric aldol reaction[1] is one ofthe most
powerful methods for constructing carbon-carbon stereocontrol may be expected. This approach is par-
bonds in organic synthesis. Asymmetric organocataly- ticularly attractive in view ofthe ready availability of
sis has progressed at an astonishing pace in recent natural amino acids and ofthe various chiral structur-
years.[2] A wide range ofsmall organic molecules, in-
cluding proline[3] and various other chiral pyrrolidine
al scaffolds that they can offer.
Serine and threonine seem to be good chiral structur-
derivatives,[4] have been shown to be efficient catalysts al scaffolds, as the hydroxy group allows for the easy at-
for asymmetric aldol reactions. Proline and its ana- tachment ofvarious hydrophobic groups. We prepared
logues are believed to catalyze the direct aldol reac- bulky siloxy derivatives ofserine and threonine, and
tion via the enamine mechanism, which mimics the screened these catalysts in the direct aldol reactions be-
action ofnatural class I aldolase. However, the vast
majority oforganocatalytic reactions would yield rac-
emic products ifthe reactions took place in water.
tween cyclohexanone and benzaldehyde in water
(Table 1). Natural serine or threonine, as well as other
hydrophobic amino acids such as valine, leucine and
[5]
Water is an ideal solvent for chemical reactions due isoleucine were not efficient organocatalysts (entries 1
to its low cost, safety and environmentally benign to 5). The incorporation ofhydrophobic siloxy groups
nature. Since the seminal contribution from Breslow into serine and threonine resulted in effective organoca-
on the unusual rate acceleration ofthe Diels–Alder
talysts capable ofcatalyzing the direct aldol reaction in
reaction in water,[6] aqueous organic chemistry has water (entries 6 to 11). Among the three siloxy deriva-
gained more and more recognition.[7] Recently, it was tives, the catalysts containing the tert-butyldimethylsilyl
shown by the groups ofTakabe, Barbas and Hayashi
(TBS) group gave the best yield and enantioselectivity.
that the direct asymmetric aldol reaction and the Mi- The threonine derivative 2c turned out to be the most
chael reaction could be catalyzed by the proline-de- efficient catalyst. With 2 mol% catalyst loading, the de-
rived hydrophobic catalysts in water.[8] Cordova et al. sired aldol product was obtained in about 60% yield
demonstrated that acyclic amino acids or small pep- and with 96% ee in less than two days (entry 12).
tides could effect direct aldol reactions in an aqueous When the reaction was carried out neat, both yield and
system.[9] We recently reported the tryptophan-pro- diastereoselectivity decreased (entry 13).
812
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Organocatalysts for Direct Asymmetric Aldol Reactions in Water
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[a]
Table 1. Screening oforganocatalysts.
Entry
Catalyst
Catalyst Loading [%]
Time [h]
Yield[b] [%]
anti:syn[c]
ee[d] [%]
1
2
3
4
5
6
7
8
l-Ser
l-Thr
l-Val
l-Leu
l-Ile
1a
1b
1c
2a
2b
10
10
10
10
10
10
10
10
10
10
10
2
48
48
48
48
48
48
24
24
36
36
18
45
45
<5[e]
<5[e]
<5[e]
<10[e]
<10[e]
49
23
65
41
34
-
-
-
-
-
-
-
-
-
-
4:1
2:1
7:1
3:1
2:1
8:1
8:1
5:1
42
13
89
13
10
96
96
96
9
10
11
12[f]
13[g]
2c
2c
2c
66
58
40
2
[a]
The reactions were performed with benzaldehyde (0.5 mmol), cyclohexanone (2.5 mmol) and catalyst (0.05 mmol) in
water (5 mmol) at room temperature.
Isolated yield.
The anti to syn ratio was determined by H NMR analysis ofthe crude product.
[b]
[c]
[d]
[e]
[f]
1
The ee value ofthe anti-isomer was determined by chiral HPLC analysis.
1
Estimated by H NMR analysis ofthe crude mixture.
Aldehyde/cyclohexanone/water/catalyst ratio was 1/2/1/0.02.
The reaction was performed neat.
[g]
The hydrophobic catalyst 2c proved to be remarka- acceptors in our method are limited to aryl aldehydes,
bly effective (Table 2). In the presence of only 2 since we were unable to obtain satisfactory results
mol% ofcatalyst 2c, most reactions between cyclo- with aliphatic aldehydes.
hexanone and various aromatic aldehydes afforded
The catalytic efficiency of our catalysts is notewor-
the aldol products in excellent yield and nearly per- thy. Such catalysts may be very suitable for large-
fect ee in aqua. For the substrates with electron-do- scale preparations.[14] Moreover, the hydrophobic cat-
nating groups, a slightly higher catalyst loading (5%) alysts reported herein may be recycled and reused
was needed to promote the reaction rate (entries 9 (Table 4).[15] For instance, the recycled 2c was able to
and 10).
We next attempted to broaden the substrate scope out any decrease in yield and stereoselectivity.
to include acyclic and functionalized ketones Although the reaction mechanism is unclear at the
catalyze the aldol reactions in up to three runs with-
(Table 3). Hydroxyacetone is a useful donor substrate moment, the transition states ofthe reactions de-
as its aldol reactions provide an easy access to scribed in this account may be similar to the one de-
diols.[12] The direct aldol reaction between hydroxy- picted in our previous report.[10] The hydrophobic
acetone and para-nitrobenzaldehyde in water was in- siloxy groups were expected to stack closely to the ar-
effective (entry 1), this is not surprising since hydroxy- omatic ring ofthe substrates due to the hydrophobic
acetone is rather hydrophilic. Protection ofthe rfee
interactions. The carboxylic acid group ofthe catalyst
hydroxy function with the TBS group furnished a hy- facilitates the formation of a defined transition state
drophobic substrate, which then efficiently reacted by forming hydrogen bonds with the substrate.[16]
with the aldehyde in aqua. All three threonine-de-
In summary, we have developed a series ofhighly
rived hydrophobic catalysts were effective, affording efficient hydrophobic catalysts for direct aldol reac-
the aldol products in excellent enantiomeric excess tions in water by the simple derivatization ofnatural
(entries 2 to 4). The reactions are also applicable to threonine. The reactions described in this report are
other aromatic aldehydes (entries 6 to 8). Currently, highly enantioselective, environmentally benign and
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813

Xiaoyu Wu et al.
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Table 2. Organocatalyst 2c-catalyzed direct aldol reactions in water.[a]
Entry
Product
Time [h]
Yield[b] [%]
anti:syn[c]
ee[d] [%]
1
4 (R=p-NO2-C6H4)
4 (R=p-NO2-C6H4)
5 (R=o-NO2-C6H4)
6 (R=m-NO2-C6H4)
7 (R=p-CN-C6H4)
8 (R=p-Br-C6H4)
9 (R=2-naphthyl)
10 (R=1-naphthyl)
11 (R=p-OMe-C6H4)
12 (R=m-OMe-C6H4)
20
24
24
24
48
48
48
48
48
48
99
99
97
95
97
98
82
56
54
71
10:1
4:1
19:1
11:1
5:1
5:1
9:1
4:1
5:1
96
96
99
99
96
95
96
97
93
91
2[e]
3
4
5
6
7
8
9[f]
10[f]
5:1
[a]
The reactions were performed with aldehyde (1 mmol), cyclohexanone (2 mmol) and 2c (0.02 mmol) in water (1 mmol)
at room temperature.
Isolated yield.
The anti to syn ratio was determined by H NMR analysis ofthe crude product.
The ee value ofthe anti-isomer was determined by chiral HPLC analysis.
The reaction was carried out neat.
[b]
[c]
[d]
[e]
[f]
1
5 mol% catalyst was used.
Table 3. The direct aldol reactions ofhydroxyacetone with various aromatic aldehydes in water. [a]
Entry
Product
Catalyst/Loading [%]
Time [h]
Yield[b] [%]
anti:syn[c]
ee[d] [%]
1
2
3
4
5
6
7
8
13 (R1 =H, R2 =NO2)
2c/10
2c/10
2b/10
2a/10
2b/2
2b/2
2b/5
96
18
6
4
6
23
20
30
<5
91
92
95
92
91
76
80
-
-
14 (R1 =TBS, R2 =NO2)
1:7
1:8
1:7
1:6
1:7
1:3
1:4
97
98
97
95
96
91
92
14
14
14
15 (R1 =TBS, R2 =CN)
16 (R1 =TBS, R2 =H)
17 (R1 =TBS, R2 =Cl)
2b/2
[a]
The reactions were performed with aldehyde (0.25 mmol), hydroxyacetone (0.5 mmol) in water (3.75 mmol) at room tem-
perature.
Isolated yield.
[b]
[c]
[d]
1
The anti to syn ratio was determined by H NMR analysis ofthe crude product.
The ee value ofthe syn-isomer was determined by chiral HPLC analysis, the absolute configuration was determined by
chiral HPLC analysis ofdesilylated 16, comparing with the literature data.[13]
operationally simple. Our findings represent a novel Experimental Section
application ofprimary amino acids as asymmetric or-
ganocatalysts in aqueous organic reactions. Mechanis- Representative Procedure
tic studies, the development ofcatalytic systems appli-
To a mixture ofcatalyst 2c (4.6 mg, 0.02 mmol) and cyclo-
cable to a broader range ofsubstrates and the exten-
sion ofour catalysts to other organic transof rmations
are currently being investigated in our laboratory, and
will be reported in due course.
hexanone (0.2 mL, 2 mmol) were added benzaldehyde
(102 mL, 1 mmol) and water (18 mL, 1 mmol). The resulting
mixture was stirred at room temperature under an atmos-
phere ofargon ofr 45 h. The reaction mixture was diluted
with ethyl acetate and filtered through silica gel (1 g) to
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Organocatalysts for Direct Asymmetric Aldol Reactions in Water
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Table 4. The recycling ofcatalyst 2c.[a]
2003, 125, 5262; d) Z. Tang, F. Jiang, X. Cui, L.-Z.
Gong, A.-Q. Mi, Y.-Z. Jiang, Y.-D. Wu, Proc. Natl.
Acad. Sci. USA 2004, 101, 5755; e) Z. Tang, Z.-H.
Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang, L.-
Z. Gong, J. Am. Chem. Soc. 2005, 127, 9285; f) A. Ber-
kessel, B. Koch, J. Lex, Adv. Synth. Catal. 2004, 346,
1141; for reviews, see: g) B. List, Synlett 2001, 1675;
h) B. List, Acc. Chem. Res. 2004, 37, 548; i) W. Notz, F.
Tanaka, C. F. Barbas, III, Acc. Chem. Res. 2004, 37,
580.
Run
Time [h]
Yield[b] [%]
anti:syn[c]
ee[d] [%]
1
2
3
4
20
24
36
48
60
61
63
33
8:1
7:1
7:1
5:1
96
97
95
96
[a]
The reactions were performed with benzaldehyde
(4 mmol), cyclohexanone (16 mmol) and 2c (0.2 mmol) in
water (4 mmol) at room temperature.
[5] a) A. Cordova, W. Notz, C. F. Barbas, III, Chem.
Commun. 2002, 3024; b) K. Sakthivel, W. Notz, T. Bui,
C. F. Barbas, III, J. Am. Chem. Soc. 2001, 123, 5260.
[6] a) D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980,
102, 7816; b) R. Breslow, Acc. Chem. Res. 1991, 24,
159.
[b]
[c]
Isolated yield.
1
The anti to syn ratio was determined by H NMR analy-
sis ofthe crude product.
The ee value ofthe anti-isomer was determined by chiral
HPLC analysis.
[d]
[7] a) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751; b) C.-
J. Li, Chem. Rev. 2005, 105, 2751; c) Organic Synthesis
in Water, (Ed.: P. Grieco), Blackie, London, 1998;
d) C.-J. Li, T.-H. Chan, Organic Reactions in Aqueous
Media, Wiley, New York, 1997.
remove the catalyst. The solvent was removed under
vacuum to afford the crude product as a pale yellow oil,
which was purified by column chromatography (ethyl aceta-
te:hexane=1:10 to 1:5) to afford 3 as a colorless oil; yield:
117 mg (58%); anti:syn=8:1. The ee ofthe anti isomer was
96% [by chiral HPLC analysis using a chiralcel AS-H
column, l =210 nm, i-PrOH:hexane=5:95, 0.5 mLminÀ1,
tR =33.45 min (major), tR =35.58 min (minor)]. 1H NMR
(300 MHz, CDCl3): d=1.25–1.30 (m, 1H), 1.59–1.90 (m,
4H), 2.05–2.20 (m, 1H), 2.35–2.75 (m, 3H), 4.80–4.85 (d, J=
8.4 Hz, 1H), 7.30–7.45 (m, 5H).
[8] a) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F.
Tanaka, C. F. Barbas, III, J. Am. Chem. Soc. 2006, 128,
734; b) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh,
T. Urushima, M. Shoji, Angew. Chem. 2006, 118, 972;
Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Ur-
ushima, M. Shoji, Angew. Chem. Int. Ed. 2006, 45, 958;
c) N. Mase, K. Watanabe, H. Yoda, K. Takabe, F.
Tanaka, C. F. Barbas, III, J. Am. Chem. Soc. 2006, 128,
4966; d) Y. Hayashi, S. Aratake, T. Okano, J. Takaha-
shi, T. Sumiya, M. Shoji, Angew. Chem. 2006, 118,
5653; Y. Hayashi, S. Aratake, T. Okano, J. Takahashi,
T. Sumiya, M. Shoji, Angew. Chem. Int. Ed. 2006, 45,
5527.
Supporting Information
General methods, procedures for the preparation of the sub-
1
strates and the H NMR ofall the ifnal products are avail-
able as Supporting Information.
[9] a) A. Cordova, W. Zou, I. Ibrahem, E. Reyes, M.
Engqvist, W.-W. Liao, Chem. Commun. 2005, 3586;
b) W. Zou, I. Ibrahem, P. Dziedzic, H. Sunden, A. Cor-
dova, Chem. Commun. 2005, 4946; c) Y. Xu, A. Cordo-
va, Chem. Commun. 2006, 460; d) P. Dziedzic, W. Zou,
J. Hafren, A. Cordova, Org. Biomol. Chem. 2006, 4, 38;
e) A. Cordova, W. Zou, P. Dziedzic, I. Ibrahem, E.
Reyes, Y. Xu, Chem. Eur. J. 2006, 12, 5383.
Acknowledgements
We thank the National University of Singapore for generous
financial support.
[10] Z. Jiang, Z. Liang, X. Wu, Y. Lu, Chem. Commun.
2006, 2801.
References
[11] For the use ofhydrophobicity in organic synthesis, see:
a) U. M. Lindstrom, F. Andersson, Angew. Chem. 2006,
118, 562; U. M. Lindstrom, F. Andersson, Angew.
Chem. Int. Ed. 2006, 45, 548; b) S. Otto, J. B. F. N. Eng-
berts, Org. Biomol. Chem. 2003, 1, 2809; c) R. Breslow,
Acc. Chem. Res. 2004, 37, 471.
[12] For selected examples ofaldol reactions employing hy-
droxyacetone, see: a) C. F. Barbas, III, A. Heine, G.
Zhong, T. Hoffmann, S. Gramatikova, R. Bjornestedt,
B. List, J. Anderson, E. A. Stura, I. A. Wilson, R.
Lerner, Science 1997, 278, 2085; b) W. Notz, B. List, J.
Am. Chem. Soc. 2000, 122, 7386; c) K. Sakthivel, W.
Notz, T. Bui, C. F. Barbas, III, J. Am. Chem. Soc.
2001, 123, 5260; d) Z. Tang, Z.-H. Yang, L.-F. Cun, L.-
Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Org. Lett. 2004, 6,
2285.
[1] Modern Aldol Reactions, Vols. 1 and 2, (Ed.: R. Mahr-
wald), Wiley-VCH, Weinheim, 2004.
[2] a) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248; P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed.
2004, 43, 5138; b) A. Berkssel, H. Grçger, Asymmetric
Organocatalysis, Wiley-VCH, Weinheim, 2005.
[3] a) B. List, R. A. Lerner, C. F. Barbas, III, J. Am.
Chem. Soc. 2000, 122, 2395; b) W. Notz, B. List, J. Am.
Chem. Soc. 2000, 122, 7386.
[4] For selected examples, see: a) H. Torii, M. Nakadai, K.
Ishihara, S. Saito, H. Yamamoto, Angew. Chem. 2004,
116, 2017; H. Torii, M. Nakadai, K. Ishihara, S. Saito,
H. Yamamoto, Angew. Chem. Int. Ed. 2004, 43, 1983;
b) S. Saito, H. Yamamoto, Acc. Chem. Res. 2004, 37,
570; c) Z. Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong,
A.-Q. Mi, Y.-Z. Jiang, Y.-D. Wu, J. Am. Chem. Soc.
[13] P. J. Walsh, K. B. Sharpless, Synlett 1993, 605.
Adv. Synth. Catal. 2007, 349, 812 – 816
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www.asc.wiley-vch.de
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Xiaoyu Wu et al.
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[14] In an illustrative example, in the presence of40 mg of
2c, 2 g ofcompound 4 with 96% ee was obtained after
a single recrystallization.
[16] A. Bassan, W. Zou, E. Reyes, F. Himo, A. Cordova,
Angew. Chem. 2005, 117, 7190; A. Bassan, W. Zou, E.
Reyes, F. Himo, A. Cordova, Angew. Chem. Int. Ed.
2005, 44, 7028.
[15] See Supporting Information for details.
816
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Adv. Synth. Catal. 2007, 349, 812 – 816