An air-stable, storable chiral zirconium catalyst for asymmetric aldol reactions

Article abstract of DOI:10.1039/b305273g

Asymmetric aldol reactions of ketene silyl acetals with aldehydes using an air-stable, storable chiral zirconium catalyst, which could be stored for at least 13 weeks at room temperature, proceeded smoothly to afford the desired adducts in high yields wit

Full text of DOI:10.1039/b305273g

An air-stable, storable chiral zirconium catalyst for asymmetric aldol
reactions
Sh u¯ Kobayashi,* Susumu Saito, Masaharu Ueno and Yasuhiro Yamashita
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033,
Japan
Received (in Cambridge, UK) 14th May 2003, Accepted 17th June 2003
First published as an Advance Article on the web 3rd July 2003
Asymmetric aldol reactions of ketene silyl acetals with
aldehydes using an air-stable, storable chiral zirconium
catalyst, which could be stored for at least 13 weeks at room
temperature, proceeded smoothly to afford the desired
adducts in high yields with high selectivity.
Catalytic asymmetric carbon–carbon bond-forming reactions
with chiral catalysts provide powerful tools for construction of
the basic skeletons of optically active compounds.1 While
(1)
several excellent chiral catalysts have been developed, chiral
Lewis acids are among the most useful and promising.2
was carried out using 5 mol% of the 3I-ZrMS catalyst in toluene
at 0 °C in the presence of PrOH (80 mol%). The reaction
proceeded smoothly to afford the desired product in 74% yield
with high diastereo- and enantio-selectivities (syn/anti = 9/91,
However, these catalysts are often sensitive to moisture and/or
oxygen even in air, and they decompose rapidly in the presence
of a small amount of water. Accordingly, most chiral Lewis
acids have to be prepared in situ under strictly anhydrous
conditions just before use with often tedious handling. They can
not be stored for extended periods, and therefore, development
of air-stable and storable chiral Lewis acid catalysts is strongly
85% ee). The selectivities were improved by adding H O (10
2
mol%) (96% yield, syn/anti = 9/91, 93% ee). We then
employed the 3I-ZrMS catalyst prepared from wet MS 5A
which contained 10% (w/w) H
additional H O was not needed in any catalyst-preparation steps
to obtain high yield and selectivities (quantitative yield, syn/anti
2
O, and it was found that
3
desired. To address this issue, we have recently developed an
2
air-stable, storable chiral zirconium catalyst (ZrMS) prepared
t
from zirconium tetra-tert-butoxide (Zr(O Bu)
fluoroethyl)-1,1A-binaphthalene-2,2A-diol
4
), 6,6A-bis(penta-
(6,6A-(C BI-
9
=
5/95, 99% ee). We also investigated the effect of other
2 5 2
F )
molecular sieves, MS 3A and MS 4A; however, a slight
decrease of the enantioselectivity was observed (MS 3A: syn/
anti = 7/93, 91% ee; MS 4A: syn/anti = 7/93, 96% ee). The
result obtained using 3I-ZrMS was almost comparable to that of
the reaction using the zirconium catalyst prepared in situ. It is
noteworthy that this 3I-ZrMS catalyst was remarkably stable to
air and moisture, and that the catalyst could be stored for at least
NOL), N-methylimidazole (NMI), and powdered molecular
sieves 5A (MS 5A). ZrMS was shown to be effective for highly
enantioselective Mannich-type reactions.4 This catalyst was
stable in air at room temperature and was easy to handle without
requiring strict exclusion of moisture and oxygen, etc.†
On the other hand, catalytic asymmetric aldol reactions are
powerful tools for preparation of optically active b-hydroxy
carbonyl compounds, and are often successfully used in total
1
3 weeks at room temperature without loss of reactivity or
5
selectivity (Table 1).
synthesis of optically active natural products. Recently, we
have developed highly anti-selective asymmetric aldol reac-
The 3I-ZrMS catalyst was successfully applied to asym-
metric aldol reactions of various substrates, and the results are
summarized in Table 2. In the reactions of benzaldehyde with
other silicon enolates (2b and 2c), the 3I-ZrMS catalyst worked
well, and excellent yields and enantioselectivities were obtained
(entries 1–3). In the reactions with the ketene silyl acetal derived
from phenyl propionate (2a), anti-aldol adducts were obtained
with high diastereo- and enantio-selectivities (entry 4). The
tions of silicon enolates with aldehydes using a chiral zirconium
t
catalyst, which was prepared from Zr(O Bu)
binaphthalene-2,2A-diol (3,3A-I BINOL), primary propanol
PrOH), and a small amount of H
4
, 3,3A-diiodo-1,1A-
2
6
(
2
O in situ. While this catalyst
has attained a high level of enantioselectivity with a wide scope
of substrates, the catalyst was sensitive to water and even
moisture in air. In this communication, we describe an air-stable
and storable zirconium catalyst for practical and highly
stereoselective asymmetric aldol reactions.
Table 1 Storage of a 3I-ZrMS catalyst in the reaction of benzaldehyde (1a)
with ketene silyl acetal 2a
In the course of our investigations, we found that a
combination of a chiral zirconium catalyst and powdered
molecular sieves (MS) was important to realize storage of the
Storage
time/weeks
Ee (%)
(anti)
7
catalyst for extended periods without loss of activity. The
Yield (%) (syn/anti)b
c
Entry
zirconium catalyst with MS (3I-ZrMS) was prepared according
to the following procedure. First, a zirconium propoxide
1
2
3
4
a
0
2
6
Quantitative (5/95)
Quantitative (5/95)
Quantitative (5/95)
Quantitative (5/95)
99
99
99
99
8
propanol complex (Zr(OPr)
4
·PrOH), 3,3A-I
2
BINOL, PrOH, and
2
H O were combined in toluene at room temperature for 3 h, and
2
1
13
then MS (2.5 g mmol ) was added, and the mixture was stirred
for 5 min. After removal of the solvents under reduced pressure
at room temperature for 1 h, the 3I-ZrMS catalyst was
formed.
All reactions were performed in toluene at 0 °C for 18 h in the presence of
mol% of 3I-ZrMS catalyst and 80 mol% of propanol. The concentration
5
was 0.2 M. 3I-ZrMS catalyst was prepared from Zr(OPr)
4
-PrOH, 3,3A-
I
2
BINOL in toluene, and then all solvents were evaporated in the presence
In the first trial, we used well-dried MS 5A as a support to
prepare the 3I-ZrMS catalyst. The aldol reaction of benzalde-
hyde (1a) with ketene silyl acetal (2a), eqn. (1),
O. Determined by 1H-NMR.
b
of MS 5A containing 10% (w/w) H
2
c
Determined after acetylation.
2
016
CHEM. COMMUN., 2003, 2016–2017
This journal is © The Royal Society of Chemistry 2003

reactions of p-methoxy- and p-chloro-benzaldehyde (1b and 1c)
as well as a,b-unsaturated aldehyde (1d) with 2a also took place
with high diastereo- and enantio-selectivities (entries 5–7). In
the case of an aliphatic aldehyde (1e), a slight decrease of yield
and selectivity was observed (entry 8). It is noted that a high
level of stereocontrol was achieved in the reactions of several
aldehydes, and that anti-aldol adducts were obtained with
excellent diastereo- and enantio-selectivities.
We also found that the hetero Diels–Alder reaction of 1a with
Danishefsky’s diene 2d, eqn. (2), proceeded smoothly in the
presence of 3I-ZrMS to afford the desired product in high yield
with high enantioselectivity.10
This work was partially supported by CREST and SORST,
the Japanese Science and Technology Corporation (JST), and a
Grant-in-Aid for Scientific Research from the Japanese Society
for the Promotion of Science.
Notes and references
†
Preparation of the 3I-ZrMS catalyst: Zirconium propoxide propanol
complex (Zr(OPr) ·PrOH, 0.66 g, 1.55 mmol) was added to 3,3A-I BINOL
1.0 g, 1.86 mmol) in toluene (3.5 mL) at room temperature, and the mixture
was stirred for 3 h to form a catalyst solution. In the second vessel, MS 5A
3.87 g) was placed, and THF (10 mL) was added at room temperature.
4
2
(
(
After stirring for 5 min at the same temperature, 10% (w/w) H O (0.387 g)
2
in THF (4 mL) was added, and the mixture was stirred for a further hour.
After the solvent was evaporated under reduced pressure, toluene (5 mL)
was added. To this vessel was added the catalyst solution at room
temperature, and the mixture was stirred for 5 min. The solvents were
removed under reduced pressure at room temperature to afford the 3I-ZrMS
catalyst (5.77 g). The 3I-ZrMS was treated in air and was stored in a sealed
bottle with air.
A typical experimental procedure is described for the reaction of 1a with
2
a using the 3I-ZrMS catalyst: To a suspension of the 3I-ZrMS (74.5 mg, 5
mol%) in toluene (0.9 mL) was added PrOH (19.2 mg, 0.32 mmol) in
toluene (0.3 mL) at room temperature, and the mixture was stirred for 1 h
at the same temperature. After cooling to 0 °C, 1a (42.5 mg, 0.4 mmol) in
toluene (0.4 mL) and 2a (107 mg, 0.48 mmol) in toluene (0.4 mL) were
successively added, and the whole was stirred for 18 h at the same
temperature. The reaction was quenched with saturated aqueous sodium
(2)
bicarbonate solution, and dichloromethane (CH
organic layer was separated, and the aqueous layer was extracted with
CH Cl . The organic layers were combined and dried over anhydrous
sodium sulfate. After filtration and concentration under reduced pressure,
the crude mixture was purified by preparative thin-layer chromatography
2 2
Cl ) was added. The
In conclusion, we have developed an air-stable, storable
chiral Lewis acid catalyst (3I-ZrMS) for highly stereoselective
aldol reactions. This catalyst can be stored for more than three
months in air at room temperature without loss of activity. This
2
2
3
I-ZrMS-catalyzed asymmetric aldol reaction provides a prac-
(
SiO
2
, benzene–ethyl acetate) to afford the desired aldol adduct (103 mg,
H NMR
tical way to prepare optically active b-hydroxy carbonyl
compounds with high diastereo- and enantio-selectivities.
Further investigation to utilize this catalyst in the total synthesis
of a biologically important compound is now in progress.
quantitative yield). The diastereomer ratio was determined by
1
analysis, and the optical purity was determined by HPLC analysis using a
chiral column after acetylation.
1
Review: Catalytic Asymmetric Synthesis, 2nd edn., ed. I. Ojima, Wiley-
VCH, New York, 2000.
2 Lewis Acids in Organic Synthesis, ed. H. Yamamoto, Wiley-VCH,
Weinheim, Germany, 2000, vol. 1, p. 2.
Table 2 Asymmetric aldol reactions using the (R)-3I-ZrMS catalysta
Yield (%)
(syn/anti)
Ee (%)
(anti)
3 A stable chiral La catalyst has been reported: Y. S. Kim, S. Matsunaga,
J. Das, A. Sekine, T. Ohshima and M. Shibasaki, J. Am. Chem. Soc.,
b
c
Entry
1
RCHO
Nucleophile
2
000, 122, 6506.
4
5
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and S. Kobayashi, J. Am. Chem. Soc., 2002, 124, 3292.
7 Effects of MS on reactivity and/or selectivity were reported. For
example: (a) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H.
Masamune and K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765; (b)
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Quantitative 92
6
2d
3
1a
1a
2b
97
92
94
94
4
1a
Quantitative 99
5/95)
1
989, 1581; (c) Y. Motoyama, M. Okano, H. Narusawa, N. Mikihara, K.
(
Aoki and H. Nishiyama, Organometallics, 2001, 20, 1580; (d) S. M.
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5
6
7
2a
2a
80 (5/95)
94
8
Zr(OPr)
4
·PrOH is an economical zirconium source compared to
Zr(O Bu)
9 In some cases, H
t
Quantitative 95
8/92)
4
.
(
2
O in MS affected stereoselectivity in catalytic
asymmetric reactions: (a) G. H. Posner, H. Dai, D. S. Bull, J.-K. Lee, F.
Eydoux, Y. Ishihara, W. Welsh, N. Pryor and S. Petr Jr., J. Org. Chem.,
1
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2a
2a
94 (16/84)
65 (15/85)
98
87
996, 61, 671; (b) K. Mikami, M. Terada and T. Nakai, J. Am. Chem.
8
a
The reactions were performed in toluene at 0 °C for 18 h in the presence
of 5 mol% of 3I-ZrMS and 80 mol% PrOH, unless otherwise noted. The
concentration was 0.2 M. The 3I-ZrMS catalyst was prepared from
4 2
Zr(OPr) -PrOH and 3,3A-I BINOL with MS 5A containing 10% (w/w) of
H O. Determined by H-NMR. In the reaction with 2a, the ee was
2
determined after acetylation. Catalyst (10 mol%) was used. The
concentration was 0.1 M.
b
1
c
d
10 (a) Y. Yamashita, S. Saito, H. Ishitani and S. Kobayashi, Org. Lett.,
2
002, 4, 1221; (b) Y. Yamashita, S. Saito, H. Ishitani and S. Kobayashi,
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CHEM. COMMUN., 2003, 2016–2017
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