Al-catalyzed enantioselective alkylation of α-ketoesters by dialkylzinc reagents. Enhancement of enantioselectivity and reactivity by an achiral Lewis base additive

Article abstract of DOI:10.1021/ja053259w

An Al-catalyzed enantioselective method for additions of Me₂Zn and Et₂Zn to α-ketoesters bearing aromatic, alkenyl, and alkyl substituents is disclosed. Transformations are promoted in the presence of a readily available amino acid-b

Full text of DOI:10.1021/ja053259w

Published on Web 10/12/2005
Al-Catalyzed Enantioselective Alkylation of r-Ketoesters by
Dialkylzinc Reagents. Enhancement of Enantioselectivity and
Reactivity by an Achiral Lewis Base Additive
Laura C. Wieland, Hongbo Deng, Marc L. Snapper,* and Amir H. Hoveyda*
Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
Received May 18, 2005; E-mail: amir.hoveyda@bc.edu
Abstract: An Al-catalyzed enantioselective method for additions of Me2Zn and Et2Zn to R-ketoesters bearing
aromatic, alkenyl, and alkyl substituents is disclosed. Transformations are promoted in the presence of a
readily available amino acid-based ligand and afford the desired products in excellent yields and in up to
95% ee. Investigations described illustrate that the presence of a Lewis basic additive can lead to significant
enhancements in efficiency and enantioselectivity. A mechanistic model that provides a rationale for such
effects is provided.
Introduction
functionalizable tertiary alcohols (eq 1). The higher reactivity
of R-ketoesters may at first appear as an advantage. However,
Catalytic enantioselective addition of a carbon nucleophile
to a ketone is perhaps the most efficient approach to the
synthesis of an optically enriched tertiary alcohol. However,
development of catalytic alkylations of ketones, in contrast to
related processes involving aldehyde substrates,1 has been the
subject of relatively few reports.2,3 Efficient enantioselective
additions to ketones, as opposed to aldehydes, are significantly
more challenging; ketones are less reactive, and because of the
diminished size difference between the carbonyl substituents,
the task of achieving effective enantiotopic face differentiation
is more demanding.
with the more reactive alkylating agents (e.g., alkylmetals), such
substrates demand that the chiral catalyst provides sufficient
activity at lower temperatures; otherwise, uncatalyzed and
nonenantioselective background processes can prove detrimental
to product optical purity. Three reports have appeared regarding
catalytic asymmetric additions of Zn-based reagents to R-ke-
toesters. In one study carried out by Kozlowski and co-workers,4
chiral Ti complexes were used to effect additions of Et2Zn to
afford tertiary alcohols in up to 78% ee (-40 °C, THF). Higher
enantioselectivities were observed with ketones bearing an
aromatic substituent. Jiang and co-workers have employed chiral
amino alcohols as ligands in Zn-catalyzed enantioselective
alkynylations of aromatic R-ketoesters (up to 94% ee; 70 °C,
toluene);5 alkynylzinc reagents are prepared in situ from the
reaction of a terminal alkyne and Zn(OTf)2.6 Shibasaki et al.
have developed a related method for Zn-catalyzed asymmetric
additions of Me2Zn (up to 96% ee).7 In the latter study, high
substrate activity proves costly: slow addition (over 30 h at
-20 °C) of the alkylzinc reagent is required to minimize
uncatalyzed (nonenantioselective) alkylation. Examples of reac-
tions of the more reactive Et2Zn were not provided, and, with
one exception (substrate with alkynyl substituent), only out-
comes for reactions of aromatic substrates were disclosed.
R-Ketoesters represent a more reactive class of ketones that,
upon alkylation, provide synthetically versatile and readily
(1) For recent reviews, see: (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103,
2763-2794. (b) Pu, L. Tetrahedron 2003, 59, 9873-9886.
(2) For examples of catalytic enantioselective alkylations, arylations, and
allylations of ketones, see: (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc.
1998, 120, 445-446. (b) Ramon, D. J.; Yus, M. Tetrahedron Lett. 1998,
39, 1239-1242. (c) Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651-
5666. (d) Celina, G.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc.
2002, 124, 10970-10971. (e) Yus, M.; Ramon, D. J.; Prieto, O.
Tetrahedron: Asymmetry 2002, 13, 2291-2293. (f) Jeon, S.-J.; Walsh, P.
J. J. Am. Chem. Soc. 2003, 125, 9544-9545. (g) Yus, M.; Ramon, D. J.;
Prieto, O. Eur. J. Org. Chem. 2003, 2745-2748. (h) Yus, M.; Ramon, D.
J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103-1114. (i) Prieto,
O.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2003, 14, 1955-
1957. (j) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895-2898. (k)
Garcia, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641-3644. (l) Betancort, J.
M.; Garcia, C.; Walsh, P. J. Synlett 2004, 749-760. (m) Li, H.; Walsh, P.
J. J. Am. Chem. Soc. 2004, 126, 6538-6539. (n) Li, H.; Garcia, C.; Walsh,
P. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5425-5427. (o) Wada, R.;
Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910-
8911. (p) Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han,
Z. Org. Lett. 2004, 6, 4147-4149. (q) Jeon, S.-J.; Li, H.; Garcia, C.;
LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70, 448-455.
(3) For catalytic enantioselective aldol additions to ketones, see: (a) Evans,
D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. J. Am. Chem.
Soc. 1997, 119, 7893-7894. (b) Evans, D. A.; Burgey, C. S.; Kozlowski,
M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699. (c) Johnson,
J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335. (d) Denmark, S.
E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233-4235. (e) Langner, M.;
Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984-5987. (f) Luppi, G.;
Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J.
Org. Chem. 2005, in press.
Herein, we report an Al-catalyzed protocol for enantioselec-
tive additions of Me2Zn and Et2Zn to R-ketoesters bearing
(4) (a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781-3784. (b)
DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668-
12669.
(5) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451-3453.
9
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J. AM. CHEM. SOC. 2005, 127, 15453-15456
15453

A R T I C L E S
Wieland et al.
Table 2. Al-Catalyzed Enantioselective Reaction Et2Zn with
Table 1. Representative Data from Initial Screening of Chiral
Ligands
R-Ketoesters
entry
R
R1
time
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Bn
a
b
c
d
e
f
20 min
20 min
20 min
45 min
20 min
48 h
95
95
63
96
84
75
80
70
83
60
<5
44
39
entry
AA1
AA2
conv. (%)a
ee (%)b
t-Bu
Me
Me
Me
Me
Me
1
2
3
4
L-Thr(t-Bu)
D-Thr(t-Bu)
Gly
L-Thr(Trt)
L-Thr(Trt)
L-Thr(Trt)
Gly
3
4
5
6
>98
80
20
75
-15
-30
<10
p-OMeC6H4
p-IC6H4
o-OMeC6H4
3-furyl
87
L-Thr(t-Bu)
15
g
h
20 min
20 min
88
Me
>98c
a Determined by GLC. b Determined by chiral GLC (see the Supporting
Information for details).
a Isolated yields. b Determined by chiral GLC (see the Supporting
Information for details). For stereochemical proofs and optical rotations,
see the Supporting Information. c Percent conversion (accurate yield difficult
to measure due to product volatility).
aromatic, alkenyl, and alkyl substituents. Transformations are
promoted in the presence of a readily available chiral amino
acid-based ligand and a commercially available achiral additive
to afford the desired products in high yield and up to 95% ee.
We illustrate that the presence of a Lewis base additive leads
to enhancements in efficiency and enantioselectivity. Moreover,
a model that provides a rationale for such effects is provided.
2. Effect of Achiral Additives on Reaction Efficiency and
Enantioselectivity. Next, we examined whether an appropriate
additive,12 particularly a Lewis basic entity, could give rise to
improved reaction outcomes. We studied the effect of a number
of additives, including commercially available achiral P- and
N-oxides, on the enantioselectivity and rate of reactions of Et2-
Zn with R-ketoesters (representative data are summarized in
Table 5).
As illustrated in Table 3, we established that with 50 mol %
of diethylphosphoramidate (7),13 enantioselectivity is noticeably
improved. In certain cases, such as those shown in entries 5-8
of Table 3, such enhancements are significant. Particularly
noteworthy is the reaction of 1f, where an otherwise nonselective
(<5% ee) transformation delivers tertiary alcohol 2f in 75%
ee.
3. Catalytic Enantioselective Additions with Me2Zn. The
influence of additive 7 on enantioselectivity and reaction rate
is more pronounced in the case of transformations involving
the less reactive Me2Zn. As the results summarized in Table 4
indicate, in all cases, the desired tertiary alcohol is obtained at
a substantially higher level of optical purity and more efficiently
when 50 mol % of 7 is included in the reaction mixture. Thus,
Al-catalyzed transformations that do not proceed to completion
within 24 h and afford tertiary alcohols in 30-77% ee occur
more readily (83 to >98% conv.) and in 56-95% ee in the
presence of 7. The reaction of 1i to afford 8i in 92% ee (entry
4, Table 4) is especially noteworthy and represents a significant
improvement over the previously reported protocols (30% ee).7
4. Rationale for the Effect of Achiral Additive on Reactiv-
ity and Enantioselectivity. The above observations can be
rationalized based on seminal studies of Gutmann14 and, more
recently, Denmark.15 Thus, as depicted in Scheme 1, association
of Lewis basic additive 7 (deprotonated form shown) with the
transition metal center16 of the alkylzinc reagent (I f II)17 may
Results and Discussion
1. Identification of Optimal Catalyst through Ligand
Screening: Enantioselective Additions with Et2Zn. On the
basis of the catalyst screening methods developed in our
laboratories,8 we initiated our investigation by examining the
ability of a range of chiral amino acid-based ligands (total of
∼60) in the presence of various transition metal salts to promote
enantioselective addition of Et2Zn to R-ketoester 1a.9 These
studies led us to establish that, in the presence of 15 mol % of
Al(Oi-Pr)310 and dipeptide 3 (entry 1, Table 1), tertiary alcohol
2a can be obtained efficiently (>98% conv. after 24 h at -78
°C) and in 75% ee.11 As the representative data in Table 1
indicate, both residues must be an L or a D amino acid (entry 2
vs 1). Moreover, the presence of chirality at both amino acid
residues proves to be critical in obtaining appreciable levels of
asymmetric induction (entries 3 and 4, Table 1).
As illustrated in Table 2, R-ketoesters undergo enantioselec-
tive alkylation with 15 mol % of 3 and Al(Oi-Pr)3 to afford the
desired tertiary alcohols in 63-98% yield and up to 83% ee.
Significant levels of product optical purity are observed in all
cases, except with the reaction of 1f (entry 6, Table 2), which
requires a longer reaction time (48 h vs 20-45 min) to proceed
to >98% conv. In all reactions, adventitious ketone reduction
is not observed (<2% by 400 MHz H NMR analysis).4
1
(6) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806-1807.
(7) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2003, 42, 5489-5492.
(8) (a) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-
1671. (b) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1704-1707. (c) Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. Chem.s
Eur. J. 1998, 4, 1885-1889. (d) Hoveyda, A. H. Chem. Biol. 1998, 5,
R187-R191. (e) Hoveyda, A. H. In Handbook of Combinatorial Chemistry;
Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim,
Germany, 2002; pp 991-1016.
(12) For a review on additives in asymmetric catalysis, see: (a) Vogl, E. M.;
Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570-1577.
For examples of additives in reactions promoted by the present class of
ligands, see: (b) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun,
W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
1999, 121, 4284-4285. (c) Josephsohn, N. S.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2004, 126, 3734-3735.
(13) Amount (50 mol %) of 7 was found to be optimal (see the Supporting
Information for details).
(14) Gutmann, V. The Donor-Acceptor Approach to Molecular Interactions;
(9) See the Supporting Information for details.
(10) For Al-catalyzed enantioselective cyanation of ketones in the presence of
the same class of peptide-based ligands, see: Deng, H.; Isler, M. P.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2002, 41, 1009-
1012.
(11) There is 5-10% conv. in the absence of the chiral ligand.
Plenum Press: New York, 1978.
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15454 J. AM. CHEM. SOC. VOL. 127, NO. 44, 2005

Al-Catalyzed Enantioselective Alkylation of
R
-Ketoesters
A R T I C L E S
Table 3. Al-Catalyzed Enantioselective Reaction of Et2Zn with R-Ketoesters
without additive
with 50 mol % of 7
ee (%)b;
config.
entry
R
R1
time
yield (%)a
ee (%)b
yield (%)a
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Bn
a
b
c
d
e
f
20 min
20 min
20 min
45 min
20 min
48 h
95
95
63
96
84
87
88
98c
75
80
70
83
60
<5
44
39
98
75
95
98
98
83; (+)
86; (-)
78; (+)
89; (+)
84; (+)
75; (-)
72; (+)
56; nd
t-Bu
Me
Me
Me
Me
Me
p-OMeC6H4
p-IC6H4
o-OMeC6H4
3-furyl
92
g
h
20 min
20 min
90
Me
>98c
a Isolated yields. b Determined by chiral GLC (see the Supporting Information for details). For stereochemical proofs and optical rotations, see the Supporting
Information. nd ) not determined. c Percent conversion (accurate yield difficult to measure due to product volatility).
Table 4. Al-Catalyzed Enantioselective Reaction of Me2Zn with R-Ketoesters
without additive
conv. (%)a;
with 50 mol % of 7
conv.a;
ee (%)a;
config.
entry
R
R1
time
yield (%)
ee (%)a
yield (%)b
1
2
Ph
Ph
Me
t-Bu
Me
Me
Me
a
c
d
i
24 h
24 h
24 h
24 h
24 h
92; nd
43; nd
66; 53
93; nd
>98; 97
67
50
77
70
30
>98; 97
83; 71
98; 71
>98; 44
>98; 91
95; (-)
85; (-)
84; (-)
92; (-)
56; (-)
3c
4d
5
p-OMeC6H4
Et
PhHCdCH
j
a Determined by chiral GLC (see the Supporting Information for full details). For stereochemical proofs and optical rotations, see the Supporting Information.
b Isolated yields. c Reaction carried out at -60 °C. d Low yield is due to product volatility. nd ) not determined.
electron density at the alkyl ligands)18 and stronger Zn chelation
with the Lewis basic amide (resulting from enhanced Lewis
Table 5. Effect of Additives on Al-Catalyzed Enantioselective
Reaction of Me2Zn and Et2Zn with R-Ketoestersa
acidity of Zn). Such electronic alteration, achieved by involve-
ment of an appropriate Lewis basic additive (cf. II), would
facilitate and promote directed delivery of the alkylzinc reagent
by the AA2 moiety (vs nondirected addition, which may lead
to attack on the alternative face of the Al-bound carbonyl).
The data summarized in Table 5, regarding the effect of
various additives on the efficiency and enantioselectivity of the
addition process, indicate that the presence of acidic protons
(NH2) is critical to the effectiveness of the achiral additive (e.g.,
compare entries 3-4 and 5-6); use of dimethylphosphoramidate
does not lead to improvement of reaction efficiency or enan-
tioselectivity. One plausible explanation for this observation is
entry
(alkyl)2Zn
additive
conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
Me2Zn
Et2Zn
Me2Zn
Et2Zn
Me2Zn
Et2Zn
Me2Zn
Et2Zn
Me2Zn
Et2Zn
Me2Zn
Et2Zn
none
none
7
90
>98
>98
>98
47
>98
42
>98
80
67
75
95
83
45
75
47
90
76
77
86
74
7
Me2NPO(OEt)2
Me2NPO(OEt)2
Ph3PO
Ph3PO
(t-Bu)3PO
(t-Bu)3PO
NMO
10
11
12
>98
93
>98
(16) For coordination chemistry of Al-based complexes, see: Coordination
Chemistry of Aluminum; Robinson, G. H., Ed.; VCH: Weinheim, Germany,
1993.
NMO
(17) I and II are proposed based on previous mechanistic studies. See: (a)
Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 11594-11599. Preliminary studies indicate that the
presence of Al(+3) and Zn(+2) is required; for example, alkylations
proceed to <10% conv. to afford racemic products with EtAl(Oi-Pr)2 as
the sole metal salt.
a Conditions: 3 equiv of Et2Zn (20 min), 10 equiv of Me2Zn (24 h).
b Determined by GLC analysis. c Determined by chiral GLC (see the
Supporting Information for details).
(18) Experimental and theoretical studies suggest that Lewis base coordination
to a dialkylzinc reduces Zn-C bond order, increasing alkylmetal nucleo-
philicity. (a) Hursthouse, M. B.; Motevalli, M.; O’Brien, P.; Walsh, J. R.;
Jones, A. C. J. Mater. Chem. 1991, 1, 139-140. (b) Haarland, A.; Green,
J. G.; McGrady, G. S.; Downs, A. J.; Gullo, E.; Lyall, M. J.; Timberlake,
J.; Tutukin, A. V.; Volden, H. V. Ostby, K.-A. Dalton Trans. 2003, 4356-
4366.
lead to a beneficial redistribution of electron density, enhancing
the nucleophilicity of the alkylzinc reagent (due to build-up of
(15) Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem.
Soc. 2005, 127, 3774-3789 and references therein.
9
J. AM. CHEM. SOC. VOL. 127, NO. 44, 2005 15455

A R T I C L E S
Wieland et al.
Scheme 1. Transition State Models
previously reported procedures, the present protocol can be used
with Me2Zn and Et2Zn,20 aliphatic substrates can be alkylated
with high enantioselectivity, and slow addition of the dialkylzinc
reagents is not required. The present method affords superior
(in the case of Et2Zn) or similar enantioselectivities (in the case
of Me2Zn) compared to previously reported protocols. We have
demonstrated that in the presence of a P-oxide additive (7),
enantioselectivities and reaction rates can be improved signifi-
cantly. These studies provide a striking example of how an
external Lewis base, introduced as an additive,21 can influence
the outcome of a catalytic cycle, enhancing selectivity and
efficiency. The alternative approach would involve covalent
attachment of a Lewis basic moiety to the chiral catalyst.22,23
An advantage of the present strategy is that it allows for a more
facile reaction optimization through rapid screening of different
Lewis base additives.
Al-catalyzed enantioselective alkylations of R-ketoesters is
the newest addition to a growing list of metal-catalyzed
enantioselective C-C bond forming reactions8,10,12b,c,24 that are
promoted by readily accessible and modifiable amino acid-based
chiral ligands. Development of additional catalytic asymmetric
methods, involving this class of chiral ligands and based on
catalyst activation principles discussed above, is in progress.
Acknowledgment. Financial support was provided by the
NIH (GM-57212).
Supporting Information Available: Experimental procedures
and spectral, analytical data for all compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
that the deprotonated additive (as illustrated in II, Scheme 1)
is a significantly more effective Lewis base. Alternatively, it is
possible that 7 allows for electronic activation by association
with the alkylzinc reagent intramolecularly, as depicted in III
in Scheme 1. Through the latter mode of reaction (III), the Al-
bound additive can direct the dialkylzinc reagent toward addition
to the R-ketoester substrate. In the absence of the acidic NH
bonds, the Al-N bond cannot form, and intramolecular mode
of activation (III, Scheme 1) is no longer feasible. In certain
cases, such as entries 9 and 11, reaction efficiency and
enantioselectivity do improve with additives that most likely
do not provide two-point contact with the Al-based chiral
complex. Nonetheless, overall, the data summarized in entries
7-12 of Table 5 support the notion that to achieve the most
optimal results it may be that the additive must be able to be
converted to a highly Lewis basic entity or provide intramo-
lecular activation.19
JA053259W
(20) Reactions with the more nucleophilic Ph2Zn and (i-Pr)2Zn under the present
conditions led to >98% conv. and <2% ee, presumably due to uncatalyzed
alkylation. Studies aimed at identification of chiral catalysts that promote
a broader range of alkylations are in progress.
(21) For catalytic asymmetric reactions involving P-oxide additives, see: (a)
Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M.
Tetrahedron 2001, 57, 805-814. (b) Tian, J.; Yamagiwa, N.; Matsunaga,
S.; Shibasaki, M. Angew. Chem., Int. Ed. 2002, 41, 3636-3638. (c)
Kinoshita, T.; Okada, S.; Park, S. R.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2003, 42, 4680-4684. (d) Kino, R.; Daikai, K.; Kawanami,
T.; Furuno, H.; Inanaga, J. Org. Biol. Chem. 2004, 1822-1824. (e) Casa,
J.; Najera, C.; Sansano, J. M.; Saa, J. M. Tetrahedron 2004, 60, 10487-
10496.
(22) For representative examples, see: (a) Hamashima, Y.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 7412-7413. (b) Ogawa, C.; Sugiura,
M.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 6491-6493.
(23) For recent examples involving significant increase in reactivity and
enantioselectivity of a catalytic asymmetric C-C bond forming reaction
in the presence of a Lewis basic additive, see: Lundgren, S.; Wingstrand,
E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc. 2005, 127, 11592-11593
and references therein.
(24) For representative examples of Zr-catalyzed alkylations of alkylzinc reagents
to imines: (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M.
L. J. Am. Chem. Soc. 2001, 123, 984-985. Cu-catalyzed conjugate additions
of alkylzinc reagents to carbocyclic enones: (b) Degrado, S. J.; Mizutani,
H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755-756. Cu-catalyzed
allylic alkylations with alkylzinc reagents: (c) Luchaco-Cullis, C.-A.;
Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001,
40, 1456-1460. Cu-catalyzed conjugate additions of alkylzinc reagents to
nitroalkenes: (d) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem.
Soc. 2005, 127, 4584-4585. Cu-catalyzed conjugate additions of alkylzinc
reagents to unsaturated heterocycles: (e) Brown, M. K.; Degrado, S. J.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44, 5306-5310.
Conclusions
We have developed an Al-catalyzed method for enantiose-
lective alkylations of a variety of R-ketoesters. In contrast to
(19) Enantioselectivity measurements with chiral ligands of various degrees of
optical purity indicate that the presence of 7 does not significantly alter
the slight degree of nonlinearity observed. See the Supporting Information
for details. For an excellent review of nonlinear effects in asymmetric
catalysis, see: Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402-411.
9
15456 J. AM. CHEM. SOC. VOL. 127, NO. 44, 2005