Organocatalytic asymmetric syn-selective direct aldol reaction in ionic liquid

Article abstract of DOI:10.1246/cl.2010.490

A practical and recyclable organocatalytic strategy is developed to provide syn-selective aldol products in ionic liquid. The siloxy serine organocatalyst mediates the direct aldol reaction of TBSO-protected hydroxyacetone with a variety of aldehyde to provide the β-hydroxycarbonyl scaffolds in good yields and enantioselectivities up to 94%.

Full text of DOI:10.1246/cl.2010.490

doi:10.1246/cl.2010.490
490
Published on the web April 10, 2010
Organocatalytic Asymmetric syn-Selective Direct Aldol Reaction in Ionic Liquid
Fui-Fong Yong,1 Chai-Yun Poh,2 Guan-Leong Chua,2 and Yong-Chua Teo*1
1Natural Sciences and Science Education, National Institute of Education,
Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore
2Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
(Received February 10, 2010; CL-100143; E-mail: yongchua.teo@nie.edu.sg)
Table 1. Optimization studies on the siloxy L-serine catalyzed
A practical and recyclable organocatalytic strategy is
enantioselective direct aldol reaction in ionic liquida
developed to provide syn-selective aldol products in ionic
liquid. The siloxy serine organocatalyst mediates the direct aldol
reaction of TBSO-protected hydroxyacetone with a variety of
aldehyde to provide the ¢-hydroxycarbonyl scaffolds in good
yields and enantioselectivities up to 94%.
NH2
O
OH
O
H
TBDPSO
COOH
O
Anti Isomer
+
+
OTBS
OTBS
NO2
Ionic Liquid
NO2
Catalyst
/mol %
Yieldb syn/antic eed
Entry Ionic liquid
Additive
/%
/%
/%
Asymmetric organocatalysis has recently emerged as a
powerful tool in organic synthesis1 and excellent progress has
been achieved following the discovery of the proline-catalyzed
aldol reaction, which is the intermolecular variant of the Hajos-
Parrish-Eder-Sauer-Wiechert reaction, reported by List, Lerner,
and Barbas.2 Among them, organocatalytic direct asymmetric
aldol condensation3,4 is one of the most effective carbon-carbon
forming reactions used for synthesizing enantiomerically en-
riched ¢-hydroxycarbonyl structural units found in many
biologically active compounds such as macrolide antibiotics
and anti-cancer drugs.5 The potential of this reaction to generate
diversity and construction of useful building blocks for
numerous pharmaceuticals and natural products have attracted
attention from synthetic chemists and the pharmaceutical
industry.6
1
2
3
4
5
[hmim][BF4]
[hmim][PF6]
[hmim][BF4]
[bmim][BF4]
[bmim][BF4]
5
5
10
10
10
®
®
H2O
H2O
H2O
98
89
78
93
83
70:30 70
82:18 70
92:8
92:8
90:10 88f
90e
90e
aUnless otherwise noted, the reaction was performed with
aldehyde (0.5 mmol), ketone (1.0 mmol), and siloxy serine
organocatalyst (0.025 or 0.05 mmol) in ionic liquid (0.5 mL) at
room temperature for 20 h. bCombined yield of isolated
diastereomers. cDiastereoselectivity was determined by
1H NMR analysis of the crude reaction mixture. dEnantiomeric
excess refers to the syn-isomer and was determined by HPLC
analysis on a chiral phase. eThe reaction was carried out using
f
ionic liquid (0.4 mL) and water (0.1 mL) as additive. The
reaction was carried out with 1.1 equiv of ketone donor.
In our endeavors toward the development of environ-
mentally friendly organocatalytic strategies, we have developed
a siloxy serine catalyst that can mediate the asymmetric aldol
in water.7 As an extension to this work, we have also recently
reported the recyclability of this catalyst that uses cyclic
ketone, predominantly cyclohexanone as the aldol donor, in
[bmim][BF4] to facilitate the synthesis of anti-configured ¢-
hydroxycarbonyl scaffolds.8 This work was the first report of an
efficient recyclable primary amino acid for asymmetric reaction,
furnishing a wide variety of aldol products in good yields and
excellent enantioselectivities via biphasic system. Noteworthy is
that prior chemical functionalization of the ionic liquid9 with the
siloxy serine organocatalyst was not necessary for enabling
recyclability. The ionic liquid containing the siloxy serine
organocatalyst was recovered after a simple workup of the
reaction mixture. Based on this precedent and as part of our
program to further develop recyclable organocatalytic strategy in
ionic liquids, herein, we extend the protocol to the aldol reaction
that install syn-selective configured 1,2-diols products.
excess of 70% in [hmim][BF4] (Table 1, Entry 1). An attempt to
evaluate [PF6] counter ions gave the product in a lower yield of
89% with comparable enantiomeric excess (Entry 2). Interest-
ingly, it was observed that the presence of water as additive
enhances the enantio-control of the reaction, affording the
product with
a higher enantiomeric excess of 90% in
[hmim][BF4] (Entry 3). In summary, the optimum conditions
was achieved by using 10 mol % of the siloxy serine organo-
catalyst, ketone donor (2 equiv) in [bmim][BF4] and water as
additives at room temperature for 20 h whereupon the aldol
product was isolated in an excellent yield of 93% and an
enantiomeric excess of 90% (Entry 4). To enhance the atom
economical aspect of this current synthetic approach, the
optimized reaction was repeated with 1.1 equiv of the ketone
donor. In this experiment, the aldol product was obtained in a
good yield of 83% and excellent enantiomeric excess of 88%
(Entry 5). Similarly, no chemical functionalization or derivati-
zation was carried out to attach the siloxy serine organocatalyst
to the ionic liquid.
In our initial experiment, we investigated the siloxy serine
catalyzed aldol reaction between monoprotected TBSO-hy-
droxyacetone and 4-nitrobenzaldehyde in various ionic liquids
using a standardized protocol. The results evaluating the merits
of the various ionic liquid are shown in Table 1. The reaction
catalyzed by 5 mol % of siloxy serine organocatalyst afforded
the product in a good yield of 98% and moderate enantiomeric
Having optimized the reaction conditions, the direct aldol
reaction was extended to a series of aromatic aldehydes
as acceptors. The more reactive aromatic aldehydes with 3- or
4-nitro and 4-cyano substituents afforded the products in
high yields, excellent enantioselectivities and syn-selectivity
Chem. Lett. 2010, 39, 490-492
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

491
Table 2. The catalytic asymmetric aldol reaction catalyzed by
siloxy L-serine organocatalyst in [bmim][BF4]a
Table 3. Recycling studiesa of the siloxy L-serine catalyzed
direct aldol reaction in [bmim][BF4]
Yieldb
/%
syn/antic
/%
eed
/%
10 mol%
NH2
O
OH
O
H
R2
R1
TBDPSO
Cycle
T/h
COOH
X= BF4
O
+
anti isomer
+
OTBS
OTBS
R2
1
2
3
24
26
48
93
82
60
91:9
92:8
90:10
90
87
86
+
R1
N
N
3
Time
/h
Yieldb
/%
syn/anti c
/%
eed
/%
Entry
Product
aUnless otherwise shown, the reaction was performed with
aldehyde (0.5 mmol), ketone (1.0 mmol), siloxy serine organo-
catalyst (0.05 mmol) in [bmim][BF4] (0.4 mL), and water
(0.1 mL) at room temperature. bCombined yield of isolated
diastereomers. cDiastereoselectivity was determined by
1H NMR analysis of the reaction mixture. dEnantiomeric
excess refer to the syn-isomer and was determined by HPLC
analysis on a chiral phase.
O
OH
1
1a
1b
1c
1d
1e
1f
24
18
20
20
24
93
87
89
72
70
91:9
90
94
90
65
86
OTBS
NO2
O
O
OH
NO2
2
3
4
5
6
7
8
94:6
OTBS
OH
89:11
91:9
OTBS
OH
CN
Cl
O
In conclusion, we have developed an efficient and recycla-
ble siloxy serine organocatalyst for asymmetric syn-selective
aldol reaction in ionic liquid.10 Features worth noting include:
(1) the direct asymmetric aldol reaction proceeded efficiently in
[bmim][BF4] to afford a variety of valuable compounds from
commercially available substrates; (2) the procedure is simple
to perform and requires mild conditions; (3) the siloxy serine
organocatalyst is prepared easily and economically from
commercially available sources, with both enantiomers readily
available; (4) the yields and enantioselectivities obtained for
most of the products were similar, if not, higher as compared to
using water as the solvent; and (5) prior chemical attachment of
the siloxy serine catalyst to the ionic liquid was not needed for
the catalytic activity and recyclability of the organocatalyst.
Further extension of this catalytic system to other asymmetric
reactions is ongoing in our laboratory and the results will be
reported in due course.
OTBS
OH
O
90:10
OTBS
Br
O
OH
22
22
37
90:10
87:13
91
81
93e
OTBS
OH
O
22
22
38
86:14
82:18
81
84
1g
1h
63e
OTBS
OH
O
24
60e
81:19
78
OTBS
CH3
aUnless otherwise noted, the reaction was performed with
aldehyde (0.5 mmol), ketone (1.0 mmol), and siloxy serine
organocatalyst (0.05 mmol) in ionic liquid (0.4 mL) and water
(0.1 mL) at room temperature. bCombined yield of isolated
diastereomers. cDiastereoselectivity was determined by
1H NMR analysis of the reaction mixture. dEnantiomeric
excess refers to the syn-isomer and was determined by HPLC
analysis on a chiral phase. eReaction was carried out with
20 mol % catalyst loading.
We thank the National Institute of Education (Grant No.
RP5/06 TYC), Nanyang Technological University for their
generous financial support.
(Table 2, Entries 1-3). Moderate yields and enantiomeric excess
were achieved in the case of 4-chloro- or 4-bromobenzaldehyde
as acceptors (Entries 4 and 5). Neutral aldehydes such as
benzaldehyde and naphthaldehyde afforded moderate to high
yields with good enantio- and diastereoselectivities (Entries 6
and 7) using higher catalyst loading. The catalytic process using
a representative aldehyde with a para-electron-donating group,
afforded the product in good enantioselectivity in modest yield
(Entry 8).
Having established the practicality of this reaction, attention
was focused on the recyclability and reusability of this organo-
catalyst in the ionic liquid. After ether extraction of the product,
the ionic liquid residue was dried with nitrogen and the catalytic
system was reloaded with 4-nitrobenzaldehyde and TBSO-
hydroxyacetone for the next run. As shown in Table 3, it was
found that the solvent and catalyst system could be reused for up
to 3 times with good yields and comparable enantioselectivities
of 1a. The significant decrease in the chemical yield of the
product in the third cycle suggested that the lost of catalytic
activity might be due to the leaching of the siloxy serine catalyst
to the ether layer during the extraction procedure.
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5
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Chem. Lett. 2010, 39, 490-492
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/