Investigation of ligand loading and asymmetric amplification in CHAOx-catalyzed asymmetric diethylzinc additions

Article abstract of DOI:10.1016/j.tetasy.2003.07.022

The recently developed (cyclohexylsulfonylamino)oxazoline (CHAOx) ligand was found to provide high ee's and consistent reaction rates in the asymmetric diethylzinc addition to benzaldehyde over a remarkably large loading range of 0.05-10 mol%. Turnover numbers of 1000-2000 can be explained by the absence of a nonlinear effect and the formation of a catalytically active monomer complex. Substituents at the nitrogen donor atoms of the bidentate ligand prevent zinc-complex dimerization.

Full text of DOI:10.1016/j.tetasy.2003.07.022

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3605–3611
Investigation of ligand loading and asymmetric amplification in
CHAOx-catalyzed asymmetric diethylzinc additions
Peter Wipf,* Joshua G. Pierce and Xiaodong Wang
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 14 July 2003; accepted 25 July 2003
Abstract—The recently developed (cyclohexylsulfonylamino)oxazoline (CHAOx) ligand was found to provide high ee’s and
consistent reaction rates in the asymmetric diethylzinc addition to benzaldehyde over a remarkably large loading range of 0.05–10
mol%. Turnover numbers of 1000–2000 can be explained by the absence of a nonlinear effect and the formation of a catalytically
active monomer complex. Substituents at the nitrogen donor atoms of the bidentate ligand prevent zinc-complex dimerization.
© 2003 Elsevier Ltd. All rights reserved.
While large nonlinear effects have the practical advan-
tage of allowing the productive use of enantiomerically
impure reagents,16 the effective depletion in the concen-
tration of the catalytically active monomeric catalyst by
dimer formation can result in a dramatic decrease in
reaction rate as well as the requirement for higher
catalyst loadings.8,17–19 Ligand concentration also simi-
larly effects enantiomeric excess; when 20% ee DAIB
was diluted from 8 to 0.4 mM, while mol ratios of
reactants were kept constant, the % ee of the addition
product of dimethylzinc to benzaldehyde increased
from 68 to 83% ee before falling to 65% ee.12 Conse-
quently, typical loadings of chiral ligands for diethyl-
zinc additions to aldehydes range from 2–20 mol%.2
Most commonly, 5–10 mol% loadings are utilized,
which strongly limits the practical utility of asymmetric
zinc additions in fine chemicals production.20
1. Introduction
The mechanism of diethylzinc addition to aldehydes in
the presence of catalytic amounts of chiral amino alco-
hols has been extensively investigated.1–6 Kagan’s
studies7–10 of the nonlinear correlation of catalyst ver-
sus product enantiomeric excess have been particularly
valuable for the understanding of mechanistic effects in
this system.11–15 Noyori et al. have developed a model
that explains the exceptional nonlinear effect of the
chiral amino alcohol catalyst dimethylaminoisoborneol
(DAIB), which at 15% ee converts benzaldehyde to
(S)-1-phenylpropanol in 95% ee.12 Equilibration of
trivalent monomeric Zn catalyst species with tetravalent
dimeric complexes produces chiral d,l- as well as achiral
meso-complexes; the latter are coordinatively saturated
and largely inactive in the nucleophilic addition process
(Scheme 1). Moreover, the formation of the stable
heterodimeric meso-complex enriches the relative con-
centration of the homochiral, catalytically active spe-
cies, and a high amplification of chirality is realized
when the rate of dissociation of the heterochiral dimer
is slow compared to the rate of the reaction. An
interesting aspect of nonequilibrium monomer/dimer
partitioning was recently discussed by Blackmond et
al.:14 if the Curtin–Hammett condition for equilibrium
exchange is not met, strongly binding electron-rich
aldehyde substrates may exhibit greater asymmetric
amplification in spite of slower reaction rates.
Recently, Bra¨se and Dahmen reported that the
[2,2]paracyclophane ligand 6 provided a 92% yield of
the diethylzinc addition product to benzaldehyde in
80% ee at 0.05–0.1 mol% loading after 16 h at 0°C,21,22
which represents a significant improvement over the
past state-of-the-art in this process (Fig. 1). The authors
did not provide any information about the ability of 6
to form dimeric complexes with diethylzinc and about
the occurrence of any nonlinear asymmetric effects, but
based on the steric bulk of the paracyclophane back-
bone it is likely that dimerization is indeed disfavored
and thus chiral amplification is suppressed. Planar chi-
ral ferrocenes, for example, show a linear relationship
* Corresponding author. E-mail: pwipf@pitt.edu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.022

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P. Wipf et al. / Tetrahedron: Asymmetry 14 (2003) 3605–3611
Scheme 1. Noyori mechanism for asymmetric alkylation of aldehydes with diethylzinc.12
the ideal25 110–120° bond angle in the dinuclear DAIB-
between the product % ee and ligand ee, due to steric
hindrance in the ligand framework.23,24 However, with
the latter planar chiral ligands the effect of loading on
reaction rate and asymmetric induction was not investi-
gated, and these catalysts were used at the routine 3–5
mol% level.
Zn crystal structures (Fig. 2). The compression of the
NꢀZnꢀN bond angle should increase the reactivity at
the Zn atom, while the presence of the methanesulfonyl
group on nitrogen precludes the four-membered Zn2N2
ring necessary for dimer formation. Based on this struc-
tural analysis, ligand 7 was expected to demonstrate a
strictly linear relationship between enantiomeric purity
and product % ee, and, if our hypothesis was correct,
provide high enantiomeric excess of addition product at
very low ligand loadings without significant decrease in
catalytic efficiency. In preliminary work,26 we have
shown that at 2 mol% loading, ligand 7 provided 86%
and >98% ee in the addition of diethylzinc to benzalde-
hyde and cyclohexanecarboxaldehyde, respectively, thus
demonstrating its effectiveness in catalyzing the desired
transformation. Herein we report our results on the
study of the nonlinear and ligand loading effects of this
catalyst.
Figure 1. Highly active bidentate ligands for asymmetric
diethylzinc additions.
Since the formation of dimeric complex equilibria that
accompanies nonlinear effects reduces the concentra-
tion of the catalytically active species, we hypothesized
that highly active ligands for asymmetric diethylzinc
additions to prochiral carbonyl groups could be
obtained by restricting the flexibility of the bidentate
ligand scaffold in a fashion that would prevent forma-
tion of tetrahedral zinc species such as 2. In order to
prevent the general deactivation of the monomeric zinc
complex, the use of steric bulk for avoiding dimeriza-
tion should be kept to a minimum. Specifically, our
recently introduced cyclohexylsulfonylaminooxazoline
(CHAOx) ligand 7 appeared to be very well suited to
test this hypothesis. Due to a 1,5-positional relationship
of the two donor nitrogen atoms, which are rigidly held
in place by the 1,2-trans-disubstituted cyclohexane
chair ligand backbone, the NꢀZnꢀN bond angle of
88.4° in the six-membered chelate differs greatly from
2. Results and discussion
The preparation of (1R,2R)-N-[2-(4-isopropyl-4,5-dihy-
drooxazol-2-yl)cyclohexyl]
methanesulfonamide
(CHAOx) 7 was reported previously,26,27 and the syn-
thesis of (1S,2S)-N-[2-(4-isopropyl-4,5-dihydrooxazol-
2-yl)cyclohexyl]methanesulfonamide ent-7 employed an
analogous sequence (Scheme 2). A solution of the
fumaric acid derivative 828 in toluene was treated with
the chiral titanium catalyst29 prepared from diol 9 to
give cyclohexene 10 in 80% yield and >99% ee after
recrystallization from i-PrOH/hexanes. Saponification
of the imide, Curtius rearrangement and quenching of
the intermediate isocyanate with benzyl alcohol pro-
vided the b-amino ester 11 in 73% yield. Simultaneous
catalytic hydrogenation of the alkene and hydrogenoly-
sis of the Cbz group followed by N-mesylation and

P. Wipf et al. / Tetrahedron: Asymmetry 14 (2003) 3605–3611
3607
Figure 2. Calculated structure of the THF complex of ethylzinc and ligand 7. Complex geometry was optimized at the
B3LYP/6-31G* level using Spartan. N-Mesylation prevents Zn2N2 dimer formation.
With both enantiomers of ligand 7 in hand, the nonlin-
ear effect in the diethylzinc addition to benzaldehyde
could be evaluated (Scheme 3). As shown in Figure 3,
the enantiomeric excess of 1-phenyl-1-propanol 14
depended in a strictly linear fashion on the enan-
tiomeric excess of ligand 7; no asymmetric amplification
ester hydrolysis led to the carboxylic acid 12. Oxalyl
chloride in CH2Cl2 in the presence of a catalytic
amount of DMF was used to activate the acid, and in
situ trapping of the acid chloride with (D)-valinol fol-
lowed by cyclodehydration to the oxazoline gave the
desired ent-7 (Scheme 2).
Scheme 2. Preparation of ent-7 by catalytic asymmetric Diels–Alder reaction and Curtius rearrangement.
Scheme 3. Asymmetric addition of diethylzinc to benzaldehyde in the presence of mixtures of chiral ligands 7 and ent-7.

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P. Wipf et al. / Tetrahedron: Asymmetry 14 (2003) 3605–3611
Figure 3. Linear correlation between the enantiomeric excess of diethylzinc addition product 14 and the enantiomeric excess of
ligand 7.
was observed. The correlation coefficient for the linear
curve fitting of the ee of 14, determined by chiral HPLC
analysis, was very high (R2=0.997). A maximum ee of
88% was obtained with enantiomerically pure chiral
ligand, and for all % ee combinations of 7 a 2 mol%
catalyst loading was employed in these studies.
0.1 mol% loading, the chiral ligand maintained a con-
sistent 85–88% product ee. At 0.05% loading, the % ee
dropped to 70%, but product 14 was still formed in
85% yield. In these studies, the concentrations of benz-
aldehyde and diethylzinc were kept constant at 0.2 and
0.4 mM, respectively, and the reaction was always
quenched after 21 h at 0°C. Yields of isolated products
varied from 85 to 94% in the 0.05–10 mol% loading
range. However, at 0.02% loading of 7, the yield of 14
markedly decreased to 14%, and essentially racemic
product was isolated.
Most significantly, we found that ligand 7 was indeed
capable of providing a high level of enantioenriched
addition product over an exceptionally broad concen-
tration range (Fig. 4). Over a 50-fold range from 5 to
Figure 4. The enantiomeric excess of diethylzinc addition product 14 as a function of the loading of enantiomerically pure ligand
7.

P. Wipf et al. / Tetrahedron: Asymmetry 14 (2003) 3605–3611
3609
In a series of control experiments, we also determined if
the product % ee in this process changed as a function
of reaction time, in order to eliminate the possibility for
asymmetric autocatalysis.1 After 4, 21, and 40 h, the
enantiomeric excess of isolated 14 was consistently
determined to be 85 3% (Fig. 5). Accordingly, auto-
catalysis does not appear to effect the conclusions of
this study. This result was confirmed by performing the
diethylzinc addition reaction in the presence of 2 mol%
of (S)-14: With additional 2 mol% of chiral ligand 7,
product (S)-14 was formed as usual. In contrast, in the
absence of any added ligand 7, no product was
obtained, thus demonstrating both the need for the
chiral ligand to accelerate the addition reaction and the
inability of product to substitute for this function.
cal rotations were measured on a Perkin–Elmer 241
digital polarimeter with a sodium lamp at ambient
temperature and are reported as follows: [h]D (c g/100
mL). Analysis of the enantiomeric excess was per-
formed by chiral HPLC (Daicel Chiracel OD-H
column, flow rate 1.0 mL/min, 2% i-PrOH, 98% hex-
ane, Tr 12.5 and 16.5 min). Oven or flame dried glass-
ware was used for all experiments. The experiments
were carried out under a nitrogen atmosphere and used
the standard inert atmosphere techniques for introduc-
ing reagents and solvents. All solvents were freshly
distilled from CaH2 under a nitrogen atmosphere. All
other commercial reagents were used as received.
4.2. (1S,6S)-6-(2-Oxooxazolidine-3-carbonyl)-cyclohex-
3-enecarboxylic acid methyl ester 1030
3. Conclusions
A solution of Ti(Oi-Pr)2Cl2 (362 mg, 1.52 mmol) and
chiral diol 9 (888 mg, 1.68 mmol) in toluene (57.0 mL)
was stirred at room temperature for 1 h and then added
Our studies provide for the first time a quantitative
illustration of the limits of ligand loading as a function
of chiral amplification phenomena. We were able to
apply rational design principles to obtain a bidentate
ligand that does not lead to zinc complex dimer forma-
tion and preserves catalytic efficiency at unusually low
loadings of 0.05–0.1 mol%, thus allowing turnover
numbers in excess of 1000. For potential industrial
applications it is also important to note that the
dynamic range of this catalytic system spans a 50–100
fold loading range without any major deterioration of
product % ee or yield, which is remarkable for organo-
zinc additions to prochiral substrates. This study sup-
ports the hypothesis that catalytic efficiency can be
significantly increased if nonlinear effects are eliminated
by catalyst design.
,
to a suspension of 4 A MS (3.0 g) in toluene (57.0 mL).
The reaction mixture was cooled to 0°C. A solution of
fumaric acid derivative 8 (2.79 g, 14.0 mmol) in toluene
(78.0 mL) was added followed by addition of hexane
(96 mL, distilled) and butadiene (40 mL). The reaction
mixture was stirred at 0°C for 24 h, then additional
butadiene (40 mL) was added. Stirring was continued at
0°C for another 49 h. The solution was quenched with
H2O and extracted with EtOAc, the organic layers were
dried (MgSO4) and concentrated, and the residue was
purified by chromatography on SiO2 (EtOAc/hexanes,
15:85) to give 10 (2.71 g, 80%, after recrystallization
from i-PrOH/hexanes) as a colorless solid: [h]D=+186
1
(c 1.28, CH2Cl2); H NMR l 5.69 (AB, 2H, J=1.76,
1.76 Hz), 4.46–4.36 (m, 2H), 4.09–3.95 (m, 3H), 3.66 (s,
3H), 3.03 (dt, 1H, J=5.58, 11.5 Hz), 2.55–2.43 (m, 2H),
2.12–1.95 (m, 2H); 13C NMR l 176.1, 175.5, 153.2,
125.0, 124.9, 62.0, 51.9, 42.7, 41.2, 39.8, 28.2, 28.1.
4. Experimental
4.1. General
4.3. (1S,6S)-6-Benzyloxycarbonylaminocyclohex-3-ene-
carboxylic acid methyl ester 11
1H NMR spectra were measured in CDCl3, unless
otherwise noted (chemical shift, multiplicity (s=singlet,
d=doublet, t=triplet, q=quartet, b=broad, m=mul-
tiplet), integration, and coupling constants (Hz)). Opti-
To a solution of Diels–Alder adduct 10 (2.00 g, 7.90
mmol) in THF (105 mL, stabilized by BHT) and H2O
(30.0 mL) was added 30% H2O2 (1.80 g, 52.9 mmol)
Figure 5. The enantiomeric excess of diethylzinc addition product 14 as a function of reaction time in the presence of 2 mol% of
enantiomerically pure ligand 7. (S)-14 was isolated in 14, 91, and 91% after 4, 21, and 40 h reaction times, respectively.

3610
P. Wipf et al. / Tetrahedron: Asymmetry 14 (2003) 3605–3611
followed by addition at 0°C of LiOH·H2O (347 mg,
8.27 mmol). The reaction mixture was stirred at room
temperature for 17 h, cooled to 0°C and treated with a
1.35N solution of Na2SO3 in H2O (35.0 mL) followed
by a 0.5N solution of NaHCO3 in H2O (62.1 mL). The
organic solvent was evaporated in vacuo, and the
aqueous residue was diluted with H2O and extracted
with CH2Cl2 (4×). The aqueous layer was acidified with
5N HCl to pH 1 and extracted with EtOAc (4×). The
combined organic layers were dried (MgSO4) and con-
centrated. The residue was purified by chromatography
on SiO2 (MeOH/CH2Cl2, 5:95) to give a colorless oil. A
solution of this oil (1.25 g, 6.77 mmol) in toluene (30.0
mL) was treated with DPPA (1.87 g, 6.77 mmol) and
Et3N (0.69 g, 6.77 mmol) at room temperature. The
mixture was stirred at room temperature for 3 h,
quenched with cold H2O, extracted with Et2O (3×) and
dried (MgSO4). After concentration the residue was
dried further under vacuum (20 min) and dissolved in
toluene (30 mL). The crude acyl azide was heated at
reflux for 1.5 h. Benzyl alcohol (0.69 g, 15.0 mmol) was
added at 85°C, and the reaction mixture was stirred at
88°C overnight (12 h). The solvent was removed in
vacuo, and the residue was purified by chromatography
on SiO2 (EtOAc/hexanes, 20:80) to give 11 (1.43 g,
73%) contaminated with a trace of benzyl alcohol as a
colorless oil that was used without further purification.
4.5. (1S,2S)-2-Methanesulfonylaminocyclohexanecar-
boxylic acid (1-hydroxymethyl-2-methylpropyl)-amide
13
To a suspension of acid 12 (787 mg, 3.11 mmol) in
CH2Cl2 (15.6 mL) was added dimethyl formamide (29.5
mg, 0.404 mmol) and oxalyl chloride (590 mg, 4.64
mmol) at 0°C. The resulting mixture was stirred at
room temperature for 19 h. The solvent was removed in
vacuo and the residue was re-dissolved in CH2Cl2 (10.9
mL). A solution of
D-valinol (401 mg, 3.88 mmol) in
CH2Cl2 (4.3 mL) was treated with Et3N (941.8 mg, 9.33
mmol) and the solution of the acid chloride in CH2Cl2
(10.9 mL) at 0°C. The reaction mixture was stirred at
room temperature for 6 h and purified by chromatogra-
phy on SiO2 (acetone/CH2Cl2, 40:60) to give 13 (0.782
g) as an off-white solid contaminated with a trace of
1
D
-valinol that was used without further purification: H
NMR (CD3OD) l 3.78–3.76 (m, 1H), 3.69–3.65 (m,
2H), 3.55–3.51 (m, 1H), 3.00 (s, 3H), 2.34–2.25 (m, 2H),
2.07–1.96 (m, 2H), 1.89–1.82 (m, 2H), 1.69–1.28 (m,
4H), 1.09–1.04 (m, 6H); 13C NMR (CD3OD) l 176.7,
63.0, 57.8, 54.9, 52.8, 41.9, 35.8, 31.6, 29.6, 26.3, 25.9,
20.0, 19.1; MS (EI) m/e (relative intensity) 288 ([M−
H2O]+, 2.4), 275 (80), 245 (20), 227 (16), 204 (89), 176
(26), 150 (32), 140 (50), 127 (22), 109 (58), 81 (69), 72
(100), 56 (32); HRMS (EI) m/z calculated for
C13H24N2O3S (M−H2O) 288.1508, found 288.1499.
4.4. (1S,2S)-2-Methanesulfonylaminocyclohexanecar-
boxylic acid 12
4.6. (1S,2S)-N-[2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-
cyclohexyl methanesulfonamide ent-7
A solution of carbamate 11 (1.43 g, 4.94 mmol) in
EtOAc (54.0 mL) was treated with 10% Pd/C (175 mg,
1.64 mmol) under a hydrogen atmosphere for 3 h, then
passed through a pad of Celite. The solvent was
removed in vacuo and the residue was diluted in
CH2Cl2 (54.0 mL). The solution was treated at 0°C with
Et3N (1.68 g, 16.6 mmol) and methane sulfonyl chloride
(0.342 g, 2.99 mmol). The resulting mixture was stirred
at room temperature for 19 h, then the solvent was
removed in vacuo. The residue was purified by chro-
matography on SiO2 (EtOAc/hexanes, 30:70) to give
(1S,2S)-2-methanesulfonylaminocyclohexanecarboxylic
acid methyl ester (0.713 g, 62%) contaminated with a
trace of MsCl as a white solid that was used without
further purification. A THF–water (17.6 mL, 10:1)
solution of the methyl ester (713 mg, 3.03 mmol) was
treated with LiOH·H2O (376 mg, 8.96 mmol) at room
temperature for 26 h. The THF was evaporated in
vacuo, and the residue was diluted with H2O, acidified
to pH 1 with 5N HCl and extracted with EtOAc (3×).
The combined organic layers were dried (MgSO4) and
concentrated. The residue was purified by chromatogra-
phy on SiO2 (MeOH/CH2Cl2, 8:92) to give 12 (687mg,
65% over three steps) as a white solid: Mp 163.5–
164.2°C (MeOH/CH2Cl2); [h]D=+74.2 (c 0.95, MeOH);
IR (neat) 3295, 2936, 1725, 1294, 1218, 1148, 1120
A suspension of amide alcohol 13 (739 mg, 2.41 mmol)
and 4-(dimethylamino)pyridine (73.8 mg, 0.604 mmol)
in CH2Cl2 (35 mL) was treated with Et3N (855 mg, 8.45
mmol) and a solution of p-toluenesulfonyl chloride (781
mg, 4.09 mmol) in CH2Cl2 (15 mL). The resulting
mixture was stirred at room temperature for 41 h,
quenched with saturated aqueous NH4Cl, and extracted
with EtOAc (3×). The combined organic layers were
dried (MgSO4), concentrated and purified by chro-
matography on SiO2 (EtOAc/hexanes, 90:10) to give
ent-7 (543 mg, 78% over two steps) as a colorless solid:
Mp 93.0–94.0°C (EtOAc/hexanes); [h]D=+81.5 (c 0.9,
CH2Cl2); IR (neat) 3282, 2934, 2866, 1664, 1320, 1149,
1
997, 895, 753 cm−1; H NMR l 4.89 (d, 1H, J=7.04
Hz), 4.23 (dd, 1H, J=0.71, 8.93 Hz), 4.00–3.91 (m,
2H), 3.49–3.39 (m, 1H), 2.94 (s, 3H), 2.41 (dt, 1H,
J=3.4, 11.0 Hz), 2.36–2.25 (m, 1H), 2.05–1.94 (m, 2H),
1.85–1.55 (m, 2H), 1.42–1.20 (m, 4H), 0.97 (d, 3H,
J=6.7 Hz), 0.89 (d, 3H, J=6.7 Hz); 13C NMR l 167.9,
71.3, 70.1, 54.6, 44.5, 41.5, 34.8, 32.6, 29.6, 25.0, 24.7,
18.7, 18.1; MS (EI) m/z (relative intensity) 288 ([M]+,
1.8), 245 (14), 209 (47), 150 (28), 140 (33), 129 (22), 97
(22), 81 (48), 69 (100), 57 (95); HRMS (EI) m/z calcu-
lated for C13H24N2O3S 288.1508, found 288.1498.
4.7. 1-Phenylpropan-1-ol 14
1
cm−1; H NMR (CD3OD) l 3.54–3.44 (m, 1H), 3.00 (s,
3H), 2.36 (dt, 1H, J=3.2, 10.9 Hz), 2.23–2.21 (m, 1H),
2.12–2.07 (m, 1H), 1.91–1.80 (m, 2H), 1.69–1.30 (m,
5H); 13C NMR l (CD3OD) 178.0, 55.2, 51.0, 41.6, 35.5,
30.7, 25.9, 25.5.
A solution of benzaldehyde (159.3 mg, 1.5 mmol) and
ligand 7 (8.70 mg, 0.03 mmol) in hexane (3.60 mL) was
treated at 0°C with a 1.0 M solution of diethyl zinc in
hexanes (3.30 mL, 3.30 mmol). The reaction mixture

P. Wipf et al. / Tetrahedron: Asymmetry 14 (2003) 3605–3611
3611
was stirred at 0°C for 21 h, quenched with a 1.0 M
solution of HCl in H2O, and extracted with CH2Cl2
(3×). The combined organic layers were dried (MgSO4)
and concentrated. The residue was purified by chro-
matography on SiO2 (EtOAc/hexanes, 15:85) to give 14
12. Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 9800–9809.
13. Shibata, T.; Yamamoto, J.; Matsumoto, N.; Yonekubo,
S.; Osanai, S.; Soai, K. J. Am. Chem. Soc. 1998, 120,
12157–12158.
14. Buono, F.; Walsh, P. J.; Blackmond, D. G. J. Am. Chem.
Soc. 2002, 124, 13652–13653.
15. Wipf, P.; Jayasuriya, N.; Ribe, S. Chirality 2003, 15,
208–212.
1
(194 mg, 94%) as a colorless oil: H NMR l 7.41–7.27
(m, 5H), 4.64 (t, 1H, J=6.9 Hz), 1.95–1.70 (m, 3H),
0.96 (t, 3H, J=7.2 Hz).
16. Moeder, C. W.; Whitener, M. A.; Sowa, J. R., Jr. J. Am.
Chem. Soc. 2000, 122, 7218–7225.
17. Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402–411.
18. Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995,
117, 2363–2364.
19. Bolm, C.; Derrien, N.; Seger, A. Synlett 1996, 387–388.
20. Blaser, H.-U.; Studer, M. Chirality 1999, 11, 459–464.
21. Dahmen, S.; Bra¨se, S. Chem. Commun. 2002, 26–27.
22. For a recent report on 0.5 mol% loading of an aminose-
lenide catalyst for diethylzinc additions to benzaldehyde,
see: Braga, A. L.; Paixao, M. W.; Luedtke, D. S.; Sil-
veira, C. C.; Rodrigues, O. E. D. Org. Lett. 2003, 5,
2635–2638.
23. Bolm, C.; Muniz-Fernandez, K.; Seger, A.; Raabe, G.;
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62, 444–445.
Acknowledgements
We thank the National Science Foundation (CHE-
0078944) and Lilly & Co for support of this research.
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