Development of bifunctional salen catalysts: Rapid, chemoselective alkylations of α-ketoesters

Article abstract of DOI:10.1021/ja026498h

Lewis acid-Lewis base salen complexes have been identified as highly efficient catalysts for the addition of dialkylzincs to α-ketoesters. In contrast to aldehydes or ketones, the reaction between diethylzinc and α-ketoesters is significant in the absence of catalyst. In the presence of catalyst, the reaction rate is increased over 100-fold relative to the background. Furthermore, the reduction product, which is a major coproduct with other catalysts, is not observed with these bifunctional salens. As a result, high yields of the addition products can be obtained (57-99%). Both the Lewis acid and Lewis base portions of the catalyst are critical to the reactivity and selectivity. The two separate portions of the catalyst have been shown to function in a cooperative manner. Copyright

Full text of DOI:10.1021/ja026498h

Published on Web 10/05/2002
Development of Bifunctional Salen Catalysts: Rapid, Chemoselective
Alkylations of r-Ketoesters
Erin F. DiMauro and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
Received April 10, 2002
We have found that bifunctional Lewis acid-Lewis base salen
catalysts1 are much more reactive compared to the Noyori DAIB2
or the Nugent MIB3 catalysts in the alkylation of aldehydes2 (Figure
1). Indeed, these salen catalysts are among the fastest for this class
of reactions. 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 this reactivity difference. We
envisioned that these catalysts would also show enhanced reactivity
in the addition of dialkylzincs to R-ketoesters. The R-hydroxyesters
arising from such additions (eq 1) are versatile synthetic precursors.4
Table 1. Addition of Et2Zn to PhCOCO2Et (eq 1, M ) Zn, n ) 2,
R3 ) Ph, R4 ) Et)a
addition
conv. (%)c
entry
cat.b
T (°C)
t (h)
reductionconv. (%)c
1
2
none
none
0
-40
0
24
2
24
2
24
2
2
24
2
2
86
45
43
37
6
11
23
3
MIB‚ZnEt
MIB‚ZnEt
1‚Zn
30 (0)
25 (5)
93 (20)
99 (34)
99 (56)
36
4
-40
5
0
6
1‚Mg
-40
-40
0
0
7
1‚Ti(Oi-Pr)2
1‚V(O)(Oi-Pr)
1‚Al(Oi-Pr)
1‚Zr(Oi-Pr)2
0
8
7
9
-40
-40
2
92 (21)
45
10
3
a Addition of 1.2 equiv Et2Zn with 10 mol % cat. b Complexes with
(R,R)-1 prepared by stirring with MR2 (M ) Zn and Mg) or MY(Oi-Pr)n
(M ) Ti, V, Al, and Zr) for 5-30 min. For the Oi-Pr sources, the released
i-PrOH was removed in vacuo, and the catalyst was redissolved for the
reaction. c Determined by GC (Cyclodexâ). Enantiomeric excess (%) of
the (R) enantiomer in parentheses.
Figure 1.
For R-ketoesters, the development of a selective alkylation, is
complicated due to competing reaction pathways. Two main
products (reduction and addition) are encountered with organome-
tallics containing a â-hydrogen (eq 1).5,6
Scheme 1
Thus, several factors must be considered in developing enanti-
oselective catalysts for the reaction in eq 1. First, the catalyst must
accelerate addition faster than the uncatalyzed, racemic addition
or reduction. With aldeyhdes and ketones, this issue does not arise
since there is no uncatalyzed reaction with Et2Zn eVen at room
temperature. In contrast, the uncatalyzed reaction of Et2Zn with
R-ketoesters is rapid (Table 1, entries 1-2). Second, the catalyst
must accelerate addition to a greater degree than reduction.
Despite their success in aldehyde alkylation, we found that
DAIB-type catalysts such as MIB3 performed poorly with R-ke-
toesters7 (Table 1, entries 3-4). Thus, our investigation commenced
with the piperidine salen-metal complexes (R,R)-1‚M, which were
prepared in four simple steps (Scheme 1).
to the addition product within 2 h at -40 °C (Table 1, entries 6-7).
The V(O)(Oi-Pr), Al(Oi-Pr), and Zr(Oi-Pr)2 complexes are less
reactive and less selective (Table 1, entries 8-10).
We propose that the piperidine group plays a critical role in this
catalyst as a Lewis basic activating group. In line with this
hypothesis, the structurally similar complexes 2-5 provide com-
parable reactivity and selectivity (Figure 2, Table 2, entries 2-5).
More hindered amines are less effective for coordination of metal
species (i.e., Et2Zn) which is consistent with the decreased reactivity
of 2,6-dimethylpiperidinyl 7 (Table 2, entry 7). If the amine base
is distant from the Ti center, bifunctional activation is less likely.
This conjecture is supported by the lesser reactivity and selectivity
of quinolinyl 8 (Table 2, entry 8) compared to pyridinyl 6 (Table
2, entry 6). Replacement of the amine with nonbasic groups should
change the catalytic activity if this Lewis base causes activation.
The lesser reactivity of the Ti complex 9 (Table 2, entry 9) is
consistent with this proposal. When 2 equiv of N-methyl morpholine
are added for every equiv of 9 (Table 2, entry 10), similar results
are observed as for 9 alone. By itself, the base is not a catalyst
In the absence of a catalyst, reduction is the principal product
(86%) at 0 °C in the reaction of Et2Zn with ethyl oxo(phenyl)-
acetate (Table 1, entry 1). In contrast, 1‚Zn8 at 0 °C, affords 93%
addition with very little reduction (Table 1, entry 5). This represents
a 120-fold change in selectiVity with respect to the uncatalyzed
reaction; the salen catalysts clearly accelerate addition to a far
10,11
greater degree than reduction. The Mg9 and Ti(Oi-Pr)2
com-
plexes proved even more reactive, providing complete conversion
* To whom correspondence should be addressed. E-mail: marisa@sas.upenn.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 12668-12669
10.1021/ja026498h CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
was isolated in 96% yield (99% conv.) with 78% ee (R). After
ester hydrolysis, the corresponding R-hydroxy acid 10 could be
readily enriched to 98% ee (R) by recrystallization. For this two-
step sequence, a 70% yield of R-hydroxy acid 10 with 98% ee is
obtained.
Figure 2.
Table 2. Addition of Et2Zn to PhCOCO2Et (eq 1, M ) Zn, n ) 2,
R3 ) Ph, R4 ) Et) Using the (R,R)-Salen-Ti(Oi-Pr)2 Complexesa
In summary, Lewis acid-Lewis base salen complexes have been
identified as effective catalysts for the addition of dialkylzincs to
R-ketoesters while suppressing the accompanying reduction reac-
tion. In addition, this represents the first example of the catalytic
asymmetric addition of alkyls to R-ketoesters.13 Further work is
underway to investigate the mechanism of this reaction and to apply
the concepts behind the amino-salen catalysts to the development
of more reactive and more selective catalysts.
entry
cat.
reduction conv. (%)b
addition conv. (%)b
1
2
none
45
0
23 (0)
2
99 (56)
94 (54)
72 (54)
91 (44)
91 (57)
84 (20)c
57 (7)
3
3
3
4
4
9
5
5
0
6
6
0
7
7
10
5
8
8
Acknowledgment. Financial support of this research was
provided by the National Institutes of Health (GM59945). E.F.D.
thanks the University of Pennsylvania for a SAS Dissertation
Fellowship.
9
9
20
15
30
56 (4)c
56 (2)c
14 (0)
10
11
9 + NMMd
NMMe
a Addition of 1.2 equiv of Et2Zn with 10 mol % cat. at -40 °C for 2 h.
b Determined by GC (Cyclodexâ column). Enantiomeric excess (%) of the
(R)-enantiomer in parentheses. c (S)-Enantiomer. d 2 equiv (relative to 9)
of N-methyl morpholine added. e Same amount as in entry 10.
Supporting Information Available: Full experimental procedures
are provided (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Table 3. Addition of Et2Zn to Ketoesters (eq 1, M ) Zn, n ) 2)
Using (R,R)-2a
References
(1) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2001, 3, 3053-3056.
(2) 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., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
pp 911-922.
reduction
conv. (%)b
addition
isolated
yield (%)
3
4
entry
R
R
conv. (%)b
1
2
Ph
Et
0
0
99
99
96
96
92
98
84
57
99
99
99
99
92
p-MeO-C6H4
Et
Et
Et
Et
Et
Et
Et
(3) MIB: Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999, 1369-1370.
(4) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe
Synthesis; VCH: Weinhein, 1997.
3
p-Br-C6H4
0
4
â-naphthyl
Me
0
5
0
(5) For example, we have found that addition of EtMgBr to R-ketoesters
affords significant amounts (16-63%) of the reduction product (see
Supporting Information).
(6) For other examples of this problem, see: (a) Sugimura, H.; Watanabe, T.
Synlett 1994, 175-177. Diastereoselective additions to R-ketoesters are
often limited to MeMgX and ArMgX which do not contain â-hydrogens.
(b) Tamai, Y.; Nakano, T.; Miyano, S. J. Chem. Soc., Perkin Trans. 1
1994, 439-445. (c) Akiyama, T.; Nishimoto, H.; Ishikawa, K.; Ozaki, S.
Chem. Lett. 1992, 447-450. (d) Whitesell, J. K.; Deyo, D.; Bhattacharya,
A. J. Chem. Soc., Chem. Commun. 1983, 802.
(7) No enantioselection was seen in a prior DAIB R-ketoester alkylation:
Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.;
Hayashi, M.; Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382,
19-37.
6
i-Pr
Cy
0
7
<4
13
0
8
t-Bu
Ph
9
Me
Me
Bn
93
10
11
12
Ph
0
96c
Ph
0
Ph
t-Bu
0
a Addition of 1.2 equiv Et2Zn with 10 mol % cat. at -40 °C for 2 h.
b Determined by GC (Cyclodexâ) or HPLC (Chiracel AD). c 5 mmol
substrate, 5 mol % catalyst.
(8) For examples of salen-Zn complexes, see: (a) Morris, G. A.; Zhou, H.;
Stern, C. L.; Nguyen, S. T. Inorg. Chem. 2001, 40, 3222-3227. (b) Singer,
A. L.; Atwood, D. A. Inorg. Chim. Acta 1998, 277, 157-162.
(9) For examples of salen-Mg complexes, see: Corazza, F.; Floriani, C.;
Chiesi-Villa, A.; Guastini, C.; Ciurli, S. J. Chem. Soc., Dalton Trans.
1988, 2341-2345.
(Table 2, entry 1 vs 11). The base and titanium salen in 2-6 (Table
2, entries 2-6) clearly act in a cooperatiVe manner as evidenced
by their higher reactivity and enantioselectivity relative to entry
10 in Table 2.
(10) For examples of salen-Ti(OR)2 complexes, see: (a) Jiang, Y.; Gong, L.;
Feng, X.; Hu, W.; Pan, W.; Li, Z.; Mi, A. Tetrahedron 1997, 53, 14327-
14338. (b) Belokon, Y.; Flego, M.; Ikonnikov, N.; Moscalenko, M.; North,
M.; Orizu, C.; Tararov, V.; Tasinazzo, M. J. Chem. Soc., Perkin Trans.
1, 1997, 1293-1295. (c) Chen, H.; White, P. S.; Gagne, M. R.
Organometallics 1998, 17, 5358-5366.
(11) We have also obtained a crystal structure for an analogue of 8 which
demonstrates that coordination of the amine base to the Ti does not occur.
(12) Seebach, D.; Marti, R. E., Hintermann, T. HelV. Chim. Acta 1996, 79,
1710-1740.
We speculate that the mechanism involves ionization of an
alkoxide group to provide a five-coordinate cationic Ti species.10a,12
This hypothesis is supported by the identical results obtained when
Ti(Ot-Bu)4 is used in place of Ti(Oi-Pr)4. The lack of a nonlinear
effect (see Supporting Information) with enantioimpure 2 in this
reaction is also consistent with the proposed bifunctional activation
mechanism.
(13) Methods that use g1 equiv chiral ligand for enantioselective R-ketoester
alkylation are known, but few (see 13e) are synthetically useful. (a)
Abenhaim, D.; Boireau, G.; Sabourault, B. Tetrahedron Lett. 1980, 21,
3043-3046. (b) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura,
M. Pure Appl. Chem. 1988, 60, 1597-1606. (c) Weber, B.; Seebach, D.
Tetrahedron 1994, 50, 6117-6128. (d) Zadel, G.; Breitmaier, E. Chem.
Ber. 1994, 127, 1323-1326. (e) Yamada, K.; Tozawa, T.; Nishida, M.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1997, 70, 2301-2308. (f) Tan, L.;
Chen, C.; Tillyer, R. D.; Grabowski, E. J.; Reider, P. J. Angew. Chem.,
Int. Ed. 1999, 38, 711-713.
The scope of this reaction was examined with (R,R)-2 (Table 3)
since it affords the best combination of reactivity and selectivity.
In all cases, the catalyst greatly accelerates the addition pathway.
This catalyst also provides a moderate degree of stereochemical
control (e78% ee) in the approach of the Et2Zn to the prochiral
R-ketoesters. The best selectivity was obtained with methyl oxo-
(phenyl)acetate (eq 2). With this substrate, the addition was
performed on a 5 mmol scale using 5 mol % 2. The R-hydroxyester
JA026498H
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J. AM. CHEM. SOC. VOL. 124, NO. 43, 2002 12669