Table 1. Addition of Et2Zn to PhCOCO2Et (eq 1: R1 ) Ph,
R2 ) Et)a
reduction
addition
addition
ee
conversion conversion
catalystb
none
none
1‚Zn
1‚Mg
T (°C) t (h)
(%)c
(%)c
(%)c
1
2
3
4
5
0
-40
0
24
2
24
2
86
45
6
0
0
11
23
93
99
99
20 (R)
34 (R)
56 (R)
-40
1‚Ti(Oi-Pr)2 -40
2
Figure 1.
a Addition of 1.2 equiv of Et2Zn with 10 mol % catalyst in PhCH3.
b Complexes with 1 were prepared by stirring with MR2 (M ) Zn, Mg) or
MY(Oi-Pr)n (M ) Ti, V, Al, Zr) for 1 h. For the i-PrO sources, the released
i-PrOH was removed in vacuo and the catalyst was redissolved for the
reaction. c Determined by chiral GC (Cyclodex b). Absolute configuration
was assigned by comparison to the literature.
For R-ketoesters, the development of an enantioselective
alkylation, is complicated by competing reaction pathways.
Two main products (reduction and addition) are encountered
in the reaction with anionic organometallics containing a
â-hydrogen (eq 1).8 Thus, several factors must be considered
in developing asymmetric catalysts for the reaction in eq 1.
First, the catalyst must accelerate the addition reaction faster
than the uncatalyzed, racemic addition or reduction. With
ketones, this issue does not arise since there is no uncatalyzed
reaction with Et2Zn at room temperature. In contrast, the
uncatalyzed reaction of Et2Zn with R-ketoesters is fairly rapid
since the substrate itself can act as a chelating ligand, thereby
activating the Et2Zn (Table 1, entries 1 and 2).9 Second, the
catalyst must accelerate addition to a greater degree than
reduction. We found that the reduction pathway can be a
major contributor in the addition of EtMgBr and Et2Zn.9
Bifunctional amino salen complexes developed in our
laboratory10,11 catalyze the addition of Et2Zn to R-ketoesters
with excellent chemoselectivity for the addition product
(Table 1, entries 3-5).9 In this communication, we discuss
the degree of asymmetric induction that is conveyed by these
catalysts as well as their scope and generality. This work
represents the first asymmetric addition of alkyl nucleophiles
to R-ketoesters using a catalytic amount of a chiral additive.
Utilizing the most reactive and selective Ti(Oi-Pr)2 salen
catalyst as a starting point (Table 1, entry 5), we wished to
assess how the three remaining salen components (diamine,
pendant amine, and alkoxide) effect the reactivity and
selectivity in the addition of Et2Zn to ethyl oxo(phenyl)-
acetate. The reactivity and selectivity of titanium morpholine
catalysts containing other diamine backbones such as (R)-
BINAM (18% reduction, 18% addition with 15% ee S) and
(S,S)-1,2-diphenylethylenediamine (5% reduction, 39% ad-
dition with 38% ee S) were poor compared to those of the
(S,S)-cyclohexanediamine analogue (Table 2, entry 3).
The pendant amine of these catalysts is crucial to the
reactivity and selectivity, indicating that it may act as a Lewis
basic activating group. For example, the Ti(Oi-Pr)2 com-
plexes 2 and 3, which contain similar pendant amines
(piperidine, pyrrolidine), display comparable reactivity and
selectivity (Figure 2, Table 2, entries 1 and 2). In contrast,
analogue 4 containing the less basic morpholine is less
reactive, while analogue 5 containing the sterically smaller
dimethylamine is less selective (Table 2, entries 3 and 4).
(5) Mukaiyama aldol: (a) Evans, D. A.; Burgey, C. S.; Kozlowski, M.
C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699. Isocyanoac-
etates: (b) Ito, Y.; Sawamura, M.; Hamashima, H.; Emura, T.; Hayashi, T.
Tetrahedron Lett. 1989, 30, 4681-4684. Self-aldol: (c) Juhl, K.; Gather-
good, N.; Jorgensen, K. A. J. Chem. Soc., Chem. Commun. 2000, 2211-
2212. [2 + 2]-Cycloaddition: (d) Evans, D. A.; Janey, J. M. Org. Lett.
2001, 3, 2125-2128. Hetero-Diels-Alder: (e) Ghosh, A. K.; Shirai, M.
Tetrahedron Lett. 2001, 42, 6231-6233. Friedel-Crafts: (f) Jensen, K.
B.; Thorbauge, J.; Hazell, R. G.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2001, 40, 160-163.
(6) For reviews, see: (a) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-
824. (b) Soai, K.; Shibata, T. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfalts, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
pp 911-922.
(7) Ph2Zn: (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445-
446. Me2Zn and Et2Zn: (b) Ramon, D. J.; Yus, M. Tetrahedron 1998, 54,
5651-5666. (c) Garcia, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 10970-10971.
(8) For an example of this problem, see ref 3a. Diastereoselective
additions to R-ketoesters are often limited to MeMgX and ArMgX which
do not contain â-hydrogens (see ref 3b-d).
(9) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc., in press. For
example, EtMgBr + PhCOCO2Et at -10 °C gives 19% reduction and 60%
addition.
(10) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2001, 3, 3053-3056.
(11) We had found that bifunctional Lewis acid-Lewis base salen
catalysts were much more reactive compared to the Noyori DAIB catalysts
(see ref 9). Under comparable conditions, these salen catalysts have among
the fastest rates (catalytic in titanium) for the enantioselective addition of
dialkylzincs to aldehydes. Separation of the Lewis acid and Lewis base
sites in these salen catalysts, which is not possible in the DAIB-type catalyst,
is proposed to account for these rate differences
Figure 2.
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Org. Lett., Vol. 4, No. 22, 2002