Catalytic enantioselective Mukaiyama aldol reaction via a chiral indium(III)-pybox complex

Article abstract of DOI:10.1016/j.tetlet.2006.04.029

A chiral indium(III) complex prepared from indium triflate and a pybox ligand has been developed to give good yields and enantioselectivities (up to 92% ee) in the addition of (1-methoxy-2-methyl-propenyloxy)-trimethylsilane to various aromatic and alipha

Full text of DOI:10.1016/j.tetlet.2006.04.029

Tetrahedron Letters 47 (2006) 4267–4269
Catalytic enantioselective Mukaiyama aldol reaction via a
chiral indium(III)–pybox complex
Fan Fu, Yong-Chua Teo and Teck-Peng Loh*
School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry,
Nanyang Technological University, 1 Nanyang Walk, Blk 5, Level 3, Singapore 637616, Singapore
Received 1 March 2006; revised 26 March 2006; accepted 6 April 2006
Available online 6 May 2006
Abstract—A chiral indium(III) complex prepared from indium triflate and a pybox ligand has been developed to give good yields
and enantioselectivities (up to 92% ee) in the addition of (1-methoxy-2-methyl-propenyloxy)-trimethylsilane to various aromatic and
aliphatic aldehydes via the Mukaiyama aldol reaction.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The asymmetric Mukaiyama aldol1 reaction between
enolsilane derivatives and aldehydes constitutes one of
the most versatile synthetic methodologies for the stereo-
selective construction of optically active b-hydroxy car-
bonyl units which are important building blocks for the
construction of many natural products and pharmaceuti-
Recently, we have reported a practical catalytic asym-
metric allylation of aldehydes with allyltributylstann-
anes in the presence of an indium(III)–pybox catalyst
as a chiral Lewis acid which has proven to be efficient
4
and especially convenient. Based on this precedent,
extension of this chiral indium(III) catalytic system to
the Mukaiyama aldol reaction was undertaken. In our
initial study, we investigated the merits of various pybox
ligands for their ability to promote the enantioselec-
tive Mukaiyama aldol reaction of benzaldehyde with
(1-methoxy-2-methyl-propenyloxy)-trimethylsilane using
a standard protocol. The chiral indium complexes were
prepared by reacting indium triflate (0.2 equiv) and a ser-
ies of bis-oxazoline ligands 1–8 (0.22 equiv) in dichloro-
2
cals. Therefore, intense research in this area has been
carried out in recent years leading to the development of
numerous Lewis acid catalysts bound to chiral ligands.3
However, to the best of our knowledge, enantioselec-
tive Mukaiyama aldol reactions employing a chiral ind-
ium(III) catalyst have not been reported. Herein, we
report the first asymmetric Mukaiyama aldol reaction
between (1-methoxy-2-methyl-propenyloxy)-trimethyl-
silane and various aldehydes catalyzed by a chiral
indium(III)–pybox complex (Eq. 1).
˚
methane at room temperature in the presence of 4 A
MS. After stirring for 1 h, benzaldehyde (1.0 equiv)
was added followed by (1-methoxy-2-methyl-propen-
yloxy)-trimethylsilane (1.2 equiv). The product was
obtained by aqueous work-up and column chromatogra-
phy. The results are shown in Table 1.
pybox-In(III) complex
20 mol%)
OH
*
O
OTMS
OMe
O
(
+
R
OMe
-40 oC, 4Å MS / CH2Cl2
R
H
Investigation into the utility of the In(III)–pybox
complexes demonstrated that tridentate bis(oxazolinyl)-
pyridines (pybox) (Table 1, entries 1, 6, 7 and 8) were
effective catalysts for the enantioselective Mukaiyama
aldol reaction. Variation of the ligand substituent
revealed that the (S,S)-i-Pr-pybox–In(III) complex 1
was the optimal catalyst in this series, affording the
O
O
N
N
N
1
ð1Þ
(
S)-b-hydroxy ester in 65% ee and 86% yield (entry 1).
The bidentate (S,S)-bis-oxazoline ligands 2–5 were
ineffective catalysts for enantiocontrol of this reaction
(entries 2–5) probably due to ineffective binding of the
ligand to indium.
Keywords: Catalytic; Chiral indium complex; Enantioselective Mukai-
yama aldol.
*
Corresponding author. Tel.: +65 6790 3733; fax: +65 6316 6984;
e-mail: teckpeng@ntu.edu.sg
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.029

4268
F. Fu et al. / Tetrahedron Letters 47 (2006) 4267–4269
Table 1. Evaluation of various bis-oxazoline ligands for the enantio-
selective Mukaiyama aldol reaction
Table 2. Optimization studies for the enantioselective Mukaiyama
aldol reaction catalyzed by chiral (S,S)-i-Pr-pybox–1–In(III) complex
a
a
O
pybox-In(III) complex
(20 mol%)
OH
*
O
OTMS
OMe
O
Ligand-In(III) complex
20 mol%)
OH
*
O
OTMS
OMe
+
H
OMe
(
-40 oC, 4Å MS / CH Cl
+
2
2
H
OMe
40 oC, 4Å MS / CH Cl
-
2
2
ð2Þ
b
c
Entry Indium reagent Temperature (ꢁC) Yield (%) ee (%)
O
N
O
O
O
N
1
2
3
4
5
6
7
8
9
In(OTf)
InF
InCl
3
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ20
ꢀ60
ꢀ40
ꢀ40
ꢀ40
86
0
65
—
0
N
N
N
3
3
23
19
84
<10
85
72
82
1
2
InBr3
5
In(OTf)
In(OTf)
In(OTf)
In(OTf)
3
3
3
3
50
—
0
62
63
O
O
O
O
d
e
f
Ph
Ph
N
N
N
N
4
3
5
Ph
Ph
In(OTf)3
a
Unless otherwise specified, the reaction was carried out with (1-
methoxy-2-methyl-propenyloxy)-trimethylsilane (0.6 mmol) and
benzaldehyde (0.5 mmol) in the presence of a chiral indium(III)
O
O
O
O
Ph
Ph
N
Ph
Ph
Ph
N
N
N
N
Ph
catalyst prepared from pybox (22 mol %) and In(OTf)
3
(20 mol %) in
the presence of 15 mg powdered activated 4 A molecular sieves in
.5 mL of CH Cl
. The reaction mixture was kept for 24 h at ꢀ40 ꢁC.
Ph
Ph
6
˚
1
2
2
b
c
Isolated yield.
O
O
Refer to Supplementary data for enantiomeric excess determination.
The reaction was carried out with 1.2 equiv of TMSCl.
The reaction was carried out with 1.2 equiv of 2,6-di-tert-butyl-4-
methylpyridine.
N
d
e
O
O
N
N
N
N
N
7
8
f
Ph
Ph
The reaction was carried out with 1.2 equiv of isopropanol.
b
c
Entry
Ligand
Yield (%)
ee (%)
carried out at ꢀ60 ꢁC afforded a very low yield (entry
) while a significant decrease in enantioselectivity was
observed at ꢀ20 ꢁC (entry 5). Attempts to increase the
yield and enantioselectivity through the employment
of additives were also unsuccessful. The addition of
TMSCl probably results in the formation of a catalyti-
6
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
86
68
56
33
24
11
14
12
65
0
0
0
0
11
15
20
cally active silicon intermediate (Me SiX), which affords
3
an avenue for a competing achiral catalytic process
5
hence leading to a loss of enantioselectivity (entry 7).
a
Unless otherwise specified, the reaction was carried out with
1-methoxy-2-methyl-propenyloxy)-trimethylsilane (0.6 mmol) and
benzaldehyde (0.5 mmol) in the presence of the chiral indium(III)
catalyst prepared from chiral ligands (22 mol %) and In(OTf)
Moreover, the addition of 2,6-di-tert-butyl-4-methyl-
pyridine and isopropanol did not afford any significant
increase in enantioselectivity or yield.
(
3
˚
(
20 mol %) in the presence of 15 mg powdered activated 4 A mole-
cular sieves in 1.5 mL of CH Cl . The reaction mixture was kept for
4 h at ꢀ40 ꢁC.
Having optimized the reaction parameters, we extended
this catalytic enantioselective Mukaiyama aldol reaction
to a series of aldehydes (Eq. 3). The results are shown in
Table 3.
2
2
2
b
c
Isolated yield.
Refer to Supplementary data for enantiomeric excess determination.
Among the aromatic aldehydes employed, 4-nitro-benz-
aldehyde underwent the catalytic process to afford the b-
hydroxy ester with an excellent enantiomeric excess of
92% and a yield of 75% (Table 3, entry 2). In addition,
the Mukaiyama aldol reaction of 1-naphthyl and
2-naphthylaldehyde under the influence of the chiral
indium catalyst 1 furnished the products in comparable
enantiomeric excesses of 77% and 76%, respectively (en-
tries 5 and 6). The reaction of 3-phenyl-propionaldehyde
under the influence of the chiral indium catalyst also
afforded the product in 51% ee (entry 7). The absolute
configuration of the b-hydroxy esters was determined
by comparison of the sign of optical rotation and the
With these encouraging results, an optimization study to
enhance both the enantiomeric excess and yield of the
reaction was initiated. The merits of various indium
salts, temperature and the effects of additives were inves-
tigated. The results are shown in Table 2.
The reaction catalyzed by the (S,S)-i-Pr-pybox–1–In-
(
OTf) complex exhibited the best conversion and enan-
3
tiomeric excess (Table 2, entry 1). The corresponding
halide complexes were inferior catalysts for the reaction
and resulted in low yields and enantioselectivities. More-
over, a temperature study revealed that the reaction
6
HPLC data with literature values.

F. Fu et al. / Tetrahedron Letters 47 (2006) 4267–4269
4269
Table 3. Enantioselective Mukaiyama aldol reaction of various
aldehydes catalyzed by chiral (S,S)-i-Pr-pybox (1)–In(III) complex
2. Review: Comprehensive Organic Synthesis; Trost, B. M.,
a
Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.
3
. For representative examples, see: (a) Kobayashi, S.; Fur-
uya, M.; Ohtsubo, A.; Mukaiyama, T. Tetrahedron: Asym-
metry 1991, 2, 635–638; (b) Kobayashi, S.; Uchiro, H.;
Shiina, I.; Mukaiyama, T. Tetrahedron 1993, 49, 1761–
OTMS
OMe
pybox 1-In(III) complex
20 mol%)
O
OH
*
O
(
+
R
H
R
OMe
4
Å MS / CH2Cl2,
o
-
40 C, 24 h
1
772; (c) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J.
ð3Þ
Am. Chem. Soc. 1996, 118, 5814–5815; (d) Evans, D. A.;
Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett. 1997, 42,
7481–7484; (e) Evans, D. A.; Kozlowski, M. C.; Burgey, C.
S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119,
b
c
Entry
R
Yield (%)
ee (%)
1
2
3
4
5
6
7
Ph
86
75
71
73
50
56
40
64
92
57
65
77
76
51
7
893–7894; (f) Evans, D. A.; MacMillan, D. W. C.;
Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859–
0860; (g) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.;
2 6 4
4-NO C H
4-MeOC
4-MeC H
1-Naphthyl
2-Naphthyl
6 4
H
1
6
4
Burgey, C. S.; Campos, K. R.; Connel, B. T.; Staples, R. J.
J. Am. Chem. Soc. 1999, 121, 669–685; (h) Evans, D. A.;
Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am.
Chem. Soc. 1999, 121, 686–699; (i) Mikami, K.; Matsu-
kawa, M. J. Am. Chem. Soc. 1994, 116, 4077–4078; (j)
Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115,
2 2
PhCH CH
a
Unless otherwise specified, the reaction was carried out with
1-methoxy-2-methyl-propenyloxy)-trimethylsilane (0.6 mmol) and
benzaldehyde (0.5 mmol) in the presence of the chiral indium(III)
catalyst prepared from pybox (1) (22 mol %) and In(OTf)
(
7
6
039–7040; (k) Mikami, K. Pure Appl. Chem. 1996, 68,
39–644; (l) Keck, G. E.; Krishnamurthy, D. J. Am. Chem.
3
˚
(
20 mol %) in the presence of 15 mg powdered activated 4 A mole-
cular sieves in 1.5 mL of CH Cl . The reaction mixture was kept for
4 h at ꢀ40 ꢁC.
Soc. 1995, 117, 2363–2364; (m) Carreira, E. M.; Singer, R.
A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837–8838; (n)
Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117,
2
2
2
b
c
Isolated yield.
Refer to Supplementary data for enantiomeric excess determination.
1
2360–12361; (o) Carreira, E. M.; Singer, R. A.; Lee, W.
J. Am. Chem. Soc. 1995, 117, 3649–3650.
4
5
6
7
. Lu, J.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2004, 7,
1
59–161.
. Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117,
570–4581.
In conclusion, we have demonstrated an enantioselective
Mukaiyama aldol reaction between (1-methoxy-2-
methyl-propenyloxy)-trimethylsilane and various alde-
hydes using a catalytic amount of (S,S)-i-Pr-pybox–1–
In(III) complex. The main features of this reaction are
4
. Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S.
J. Am. Chem. Soc. 2002, 124, 3292–3302.
. Representative procedure for the enantioselective Mukai-
yama aldol reaction of aldehydes: Preparation of (S)-
methyl-3-hydroxy-2,2-dimethyl-3-phenylpropanoate. To an
oven-dried 10 mL round-bottom flask equipped with a
7
as follows: (1) the procedure is operationally simple
and can furnish a variety of b-hydroxy esters in good
yields and enantioselectivities; (2) the reaction can be
performed exclusively using commercially available
chemicals. Continuing investigations into the identity
of the catalytic species and further extension of the cat-
alytic system to other enantioselective organic transfor-
mations are in progress.
magnetic stirring bar was added In(OTf)
3
(56.2 mg,
0.1 mmol, 0.2 equiv). The solid was azeotropically dried
with anhydrous tetrahydrofuran twice (2 mL · 2) prior to
the addition of 1.5 mL of dichloromethane. (S,S)-i-Pr-
pybox 1 (33.2 mg, 0.11 mmol, 0.22 equiv) was added to the
mixture which was then stirred under nitrogen at room
temperature for 1 h. Benzaldehyde (0.05 mL, 0.5 mmol,
1
equiv) was added to the resulting mixture which was then
stirred for 10 min to afford a white suspension. The reaction
mixture was then cooled to ꢀ40 ꢁC for 15 min followed by
slow addition of (1-methoxy-2-methyl-propenyloxy)-
trimethylsilane (0.12 mL, 0.6 mmol, 1.2 equiv). The reaction
mixture was stirred at ꢀ40 ꢁC for 24 h and then quenched
with 5 mL of saturated sodium bicarbonate solution. The
aqueous layer was extracted with ether (3 · 10 mL) and the
combined organic extract was concentrated in vacuo and
treated with a mixture of THF–1 M HCl (5:1 mL) solution
for 20 min. The mixture was extracted with ether
Acknowledgements
We wish to thank the Nanyang Technological Univer-
sity, for their generous financial support.
Supplementary data
(
3 · 10 mL), dried over anhydrous magnesium sulfate,
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
filtered and concentrated in vacuo. The residual crude
product was purified via silica gel chromatography to afford
the b-hydroxy ester as a colourless oil. (65%); [a]D +13.43
2
006.04.029.
2 2
(c 8.43 w/v%, CH Cl ). The enantiomeric excess was
determined by HPLC analysis employing a Daicel Chiralcel
References and notes
OJ column (hexane:i-propanol, 98:2, 1 mL/min: t1 =
1
2
3.8 min for the S enantiomer, t = 16.67 for the R
1
. Kobayashi, S.; Fujishita, B. Y.; Mukaiyama, T. Chem. Lett.
990, 1455–1458.
enantiomer). It had been established from literature that
the S enantiomer elutes first.
6
1