7
activating the alkylzinc reagent. Therefore, the chiral catalyst
of dimethylzinc to R-ketoesters. As starting models for our
ligands we considered bifunctional amino alcohols bearing
tertiary amines, which have been extensively used as catalysts
for the enantioselective addition of dialkylzinc to aldehydes.12
We envisioned that in the competition between the chiral
ligand and the substrate to coordinate the zinc metal ion,
the chiral ligand-Zn complex may be favored by increasing
the electron-donating ability of the ligand, and this would
favor the enantioselective reaction with respect to the
competing nonenantioselective background “substrate-
catalyzed” reaction. However, it also should be kept in mind
that a too strong electron-donating coordinating group on
the ligand may decrease the Lewis acidity of the metal center,
therefore preventing coordination and activation of the
carbonyl group. We thought that deprotonated N-monosub-
stiuted carboxy amides would serve perfectly for this
purpose. Amide and carbamate type ligands have been used
by Seto as catalysts for the enantioselective addition of
must provide sufficient activity; otherwise, uncatalyzed and
nonenantioselective background reaction may be detrimental
to optical purity.
To date, only three methods for the enantioselective
addition of dialkylzinc to ketoesteres have been reported.
Kozlowski et al. have used titanium-salen type catalysts
2
obtaining good yields of Et Zn addition products with fair
8
enantioselectivities (up to 78%). Shibashaki et al. have
developed a system based on a proline-derived aminodiol.
With this system high enantioselectivities can be attained
up to 96%) with the addition of Me
reaction requires a slow addition of the reagent at low
temperature (-20 °C) and long reaction times. Et Zn was
2
completely unreactive with this system.
In the two methods mentioned above, the background
reaction is minimized by using bifunctional Lewis acid/Lewis
base (LA/LB) catalysts (Figure 1), which unlike other
(
2
Zn, although the
9
1
3
dialkyl- and vinylzinc reagents to aldehydes.
Simple mandelamides are easily prepared in one step
starting from mandelic acid and amines. We have shown
that these compounds can be used as ligands in the
asymmetric addition of dialkylzinc to aldehydes catalyzed
1
4
by titanium isopropoxide. These compounds bear a hy-
droxyl group and a N-monosubstituted carboxyamide that
may be deprotonated in the reaction media, and therefore
fulfill the requirements stated above to be used as ligands
for the addition to R-ketoesters.
The investigation started with the reaction between methyl
1
2
(
phenyl)oxoacetate 2 (R ) Ph, R ) Me) and dimethylzinc.
As is shown in Table 1, all mandelamides 1a-e were able
to catalyze the reaction at acceptable rates and with moderate
enantioselectivites. The fastest reaction was found with
mandelamides derived from benzylamine 1a and picoly-
lamine 1c (entries 1 and 4); amide 1a gave the highest
enantioselectivity under these conditions. The introduction
of an additional methyl group in the vicinity of the amide
(entries 2 and 3) or the use of N-tert-butyl amide had a
deleterious effect, and the reaction required longer reaction
times to reach completion, although the final yield and ee
did not show big variations. On the other hand, the reaction
with amino alcohol 1f (entry 9) was not complete after 24 h
and the product was obtained in only 15% ee, in good
agreement with our expectations. The reaction catalyzed by
Figure 1. Catalysts used in the addition of dialkylzinc to
R-ketoesters.
bifunctional catalysts, bear electronically decoupled LA/LB
1
0
sites. These ligands provide activation of the substrate by
a Lewis acid metal and independent Lewis base activation
of the nucleophilic reagent by a heteroatom-containing
moiety properly positioned on the ligand framework. This
double activation results in the acceleration of the catalyzed
reaction. Very recently, Hoveyda et al. have described an
Al-catalyzed enantioselective method for the addition of
dialkylzinc to R-ketoesters. Transformations are promoted
1a was carried out at different temperatures. The results had
little variation in the range between room temperature and
-20 °C, except for the reaction times required. However,
in the presence of amino acid-based ligands to afford the
products in high yields and in up to 93% ee.11 In this case,
the use of a LB additive leads to a significant improvement
in efficiency and enantioselectivity by enhancing the nu-
cleophilicity of the alkylzinc reagent.
In this Letter we report a different strategy in the design
of a catalytic system for this particular reaction, the addition
(
10) Catalysts such as Zn-amino alcohols are LA/LB interdependent
catalysts, since the LA is directly coordinate to the LB moiety.
11) Wieland, L. C.; Deng, H.; Snapper, M. L.; Hoveyda, H. J. Am. Chem.
Soc. 2005, 127, 15453-15456.
12) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49-
9. (b) Fontes, M.; Verdaguer, X.; Sol a` , L.; Peric a` s, M. A.; Riera, A. J.
(
(
6
Org. Chem. 2004, 69, 2532-2534. (c) Superchi, S.; Giorgio, E.; Scafato,
P.; Rosini, C. Tetrahedron: Asymmetry 2002, 13, 1385-1391.
(13) (a) Richmond, M. L.; Seto, C. T. J. Org. Chem. 2003, 68, 7505-
7508. (b) Sprout, C. M.; Seto, C. T. J. Org. Chem. 2003, 68, 7788-7794.
(c) Richmond, M. L.; Sprout, C. M.; Seto, C. T. J. Org. Chem. 2005, 70,
8835-8840.
(
7) Di Mauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124,
2668-12669.
8) (a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781-
784. (b) Fennie, M. W.; DiMauro, E. F.; O’Brien, E. M.; Annamalai, V.;
1
3
(
Kozlowski, M. C. Tetrahedron 2005, 61, 6249-6265.
9) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibashaki, M. Angew.
Chem., Int. Ed. 2003, 42, 5489-5492.
(
(14) Blay, G.; Fern a´ ndez, I.; Hern a´ ndez-Olmos, V.; Marco-Aleixandre,
A.; Pedro, J. R. Tetrahedron: Asymmetry 2005, 16, 1953-1958.
1288
Org. Lett., Vol. 8, No. 7, 2006