A general asymmetric aldol reaction of silyl ketene acetals derived from simple esters to aryl α-keto esters

Article abstract of DOI:10.1002/ejoc.200901086

A general, method for the enantloselective addition of O,Oketene silyl acetals made from simple esters to α-keto esters catalyzed by a CuCl ₂·bis(oxazoline) complex is reported that overcomes the limitations of the classic aldol reaction, such

Full text of DOI:10.1002/ejoc.200901086

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901086
A General Asymmetric Aldol Reaction of Silyl Ketene Acetals Derived from
Simple Esters to Aryl α-Keto Esters
Julie Le Engers[a][‡] and Brian L. Pagenkopf*[a][‡‡]
Keywords: Aldol reactions / Asymmetric catalysis / Synthetic methods / Keto esters
A general method for the enantioselective addition of O,O-
ketene silyl acetals made from simple esters to α-keto esters
catalyzed by a CuCl2·bis(oxazoline) complex is reported that
overcomes the limitations of the classic aldol reaction, such
as steric intolerance and the need for expensive thio esters.
This method excels with aryl α-keto esters and provides
products in good yield and high ee that are not readily avail-
able by alternative strategies.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
esters catalyzed by a CuCl2·bis(oxazoline) complex is re-
ported that overcomes the limitations of the classic aldol
reaction (vide supra), and provides products in good yield
and high ee that are not readily available by alternative
methods.[15–18]
Introduction
The Evans enantioselective addition of silyl enol ethers
of thioesters to α-keto esters catalyzed by copper(II) bis-
(oxazoline) complexes stands as a landmark achievement in
aldol chemistry.[1,2] However, the process is sensitive to ste-
rics and even diminutive changes to the thioester nucleo-
phile or α-keto ester structures can result in a significant
drop in ee.[3] The thioesters, which are required for good
enantioselectivity, are about a thousand times more expens-
ive than simple esters.[4] The importance of methods for the
preparation of chiral quaternary centers has driven the de-
velopment of new synthetic transformations employing α-
keto esters as substrates which overcome many of the afore-
mentioned limitations. For example, closely related methods
include the asymmetric addition of enol silanes to α-keto
esters using a AgI catalyst as reported by Snapper and Hov-
eyda,[5] and by Bolm using sulfoximines in a CuII catalyzed
system.[6] Additionally, asymmetric Henry reactions,[7] ene
reactions,[8] reductive couplings,[9] reductions[10] and alk-
ylzinc additions[11] with α-keto esters have been reported.[12]
Recently, we described new copper(II) catalysts made from
substituted aryl-bis(oxazoline) ligands that addressed some
of the steric and electronic limitations of α-keto esters in
aldol reactions with silyldienolates.[13,14] In this communica-
tion a general method for the enantioselective addition of
O,O-ketene silyl acetals made from simple esters to α-keto
Results and Discussion
The investigation began with screening a variety of Lewis
acids that have been used in Mukaiyama aldol reactions
(Table 1), with silyl ketene acetal 1 and benzyl pyruvate 2
selected as model substrates. With our ligand L3[13] the best
catalyst performance was observed with a CuCl2 catalyst
system (entry 9).[19–21]
The results in Table 2 entries 1–5 show that the product
ee is dependent on the size of the ester, with a small methyl
substituent giving the lowest ee at 71%, and both tBu and
benzyl giving 94% ee. A similar trend was observed with
the pyruvate component Table 2 (entries 5–8), where in-
creasing the size of the alkoxy pyruvate component from
Me or Et to Bn gave ee values of 89, 91 and 94%, respec-
tively. There was no reaction with the tBu substrate, pre-
sumably due to steric constraints. Currently, substituted si-
lylketene acetals are not successful.
Having observed such unusual steric tolerance, the reac-
tion scope was further explored. We were delighted to find
that the reaction could be extended to aryl α-keto esters,
and excellent enantioselectivities (92–97% ee) were ob-
served for electronically neutral or activated electron-de-
ficient arenes (Table 3, entries 1–5), including those with
halogen (entry 3) and nitro (entry 5) functional handles.
With an electron-donating methoxy group (entry 6) no re-
action was observed, presumably due to attenuated ketone
electrophilicity. Also, unsaturated glyoxylates (entry 7) af-
forded good enantioselectivities (97% ee). Entry 8 demon-
strates compatibility with benzothiophene containing sub-
[a] The University of Texas at Austin, Department of Chemistry,
Austin, Texas, 78712, USA
Fax: +1-519-661-3022
E-mail: bpagenko@uwo.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901086.
[‡] Current Address: Vanderbilt University Medical Center, De-
partment of Pharmacology,
Vanderbilt Program in Drug Discovery
[‡‡]Current Address: Chemistry Department, The University of
Western Ontario, 1151 Richmond Street, London, Ontario,
N6A 3K7, Canada
Eur. J. Org. Chem. 2009, 6109–6111
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6109

J. Le Engers, B. L. Pagenkopf
SHORT COMMUNICATION
Table 1. Lewis acid screening for aldol reaction of silyl ketene acetal
Table 3. Asymmetric aldol addition of aromatic glyoxylate esters.
1.
Entry
Ligand
Lewis acids
ee (%)
Yield (%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L3
L3
L3
L3
L3
L3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(SbF6)2
Mg(OTf)2
Zn(OTf)2
Sn(OTf)2
Sc(OTf)3
CuCl2
65
31
35
16
11
14
10
7
93
52
78
78
10
79
21
82
84
94
Table 2. Reaction scope with systematic steric variations.
R1 is a methyl (Table 2, entry 6), but by increasing the size
of R1 to ethyl the ee dropped to 65% (Table 4, entry 1).
Further increasing the size of the alkyl group to n-hexyl,
isobutyl or isopropyl gave ee values of 62, 54 and 35%,
respectively. However, significant improvement was ob-
served when L4 was employed (see Table 1, Figure 1 for
crystal structure), giving useful ee values ranging from 85–
70% for the ethyl to isopropyl series (Table 4, entries 1–4).
Table 4. Asymmetric aldol addition of aliphatic glyoxylate esters.
strates as well (94% ee). It should be noted that the ee val-
ues reported here are superior to those observed for the
addition of dienosilane to glyoxylates.[13]
The results with aliphatic glyoxylate esters summarized
in Table 4 are promising, but not as impressive as the selec-
tivities observed with aryl glyoxylates. Using L3 as the chi-
ral ligand, the best selectivity was found to be 89% ee when
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A General Asymmetric Aldol Reaction of Silyl Ketene Acetals
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Conclusions
The asymmetric aldol reactions of silyl ketene acetals of
inexpensive esters and aryl glyoxylates has been reported.
This catalyst system is more tolerant to structural variation
of the substrates than the corresponding thioester aldols.
Moreover, this method excels with aryl α-keto esters and is
therefore highly complementary to other synthetic strate-
gies.
[11] L. C. Weiland, H. Deng, M. L. Snapper, A. H. Hoveyda, J. Am.
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[15] For addition of silyl ketene acetals to ketones, see: K. Oisaki,
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Supporting Information (see footnote on the first page of this arti-
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spectra.
[18] S. Adachi, T. Harada, Org. Lett. 2008, 10, 4999–5001.
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Acknowledgments
We thank The Petroleum Research Fund and the Natural Sciences
and Engineering Research Council of Canada for partial financial
support. We thank Vincent Lynch for determination of the X-ray
structure. J. L. E. is grateful for a Gates Millennium Scholarship.
[21] The role that the aryl substituents play on the selectivity of the
reaction is currently unknown.
[1] a) D. A. Evans, M. C. Kozlowski, C. S. Burgey, D. W. C. Mac-
Received: September 23, 2009
Published Online: October 28, 2009
Millan, J. Am. Chem. Soc. 1997, 119, 7893–7894; b) D. A. Ev-
Eur. J. Org. Chem. 2009, 6109–6111
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