Zhu et al.
SCHEME 1
lective reductions have also been investigated.5 Chirality
amplification (observed in similar additions using other
chiral ligands and termed nonlinear effects6), as well as
self-catalysis,7 have been observed in the similar addi-
tions of dialkylzinc to aldehydes. The syntheses of new
types of chiral ligands and their behavior in enantiose-
lective syntheses continue to be important research aims.
Calculations have been used to predict the transition
state (TS) structures for dialkylzinc addition to alde-
hydes.8 Very recently, Kozlowski et al. reported that
catalysts giving low, moderate, and high ee values in the
addition of diethylzinc to benzaldehyde could easily be
distinguished using a QSSR approach based on quantum
mechanical models (PM3).8c However, studies of how free
ligand conformational equilibria might effect the observed
enantioselectivity in this addition reaction have not been
reported.
Previously, we have reported the ee values of 1-phenyl-
1-propanol produced in additions of diethylzinc to ben-
zaldehyde (eq 1) using chiral 5-p-tolyl- or 5-o-tolyl-1,3-
oxazolidine ligands, where the substituents at C-2 were
Me, Et, n-Pr, n-Bu, and n-amyl,9 respectively. The highest
ee value was achieved when n-Pr was the C-2 substituent
in both series of oxazolidine ligands. Furthermore, dif-
ferences in ee values for diethylzinc/benzaldehyde addi-
tions have been observed9c using chiral amino alcohol
ligands, substituted on N with various linear aliphatic
substituents (methyl, ethyl, n-propyl, and n-butyl).
These ligands include three series of chiral 1,2,3,4-
tetrahydro-â-carboline ligands, 4a-d, 6a-d, and 7a-d,
where the C-1 ring substituent is n-propyl, 2-methylpro-
pyl, and phenyl, respectively, and the R groups at the
C-3 alcohol substituent for each series are (a) methyl,
(b) ethyl, (c) n-propyl, and (d) n-butyl. In addition, two
series of chiral 2,5,5-alkyl-substituted 4-(3-indolymethyl)-
1,3-oxazolidine ligands, 8a-d and 9a-g, were employed.
In oxazolidine series 8, the ring substituent at C-2 was
isopropyl and the C-5 substituents were (a) methyl, (b)
ethyl, (c) n-propyl, and (d) n-butyl, respectively. In the
oxazolidine ligand series 9, two ethyl groups were located
at C-5 and the C-2 substituents were (a) methyl, (b)ethyl,
(c) n-propyl, (d) n-butyl, (e) n-amyl, (f) 2-methylpropyl,
and (g) 2,2-dimethylpropyl, respectively. We found that
the ee values observed in the diethylzinc additions varied
using ligands 4a-d, 6a-d, and 7a-d as the R groups
on the C-3 alcohol substituent changed from methyl to
ethyl to n-propyl and to n-butyl. The TS structure 10,
containing two zinc atoms, was invoked in accord with
previous studies. A regular alternation in the ee values
was also observed upon systematically changing the C-5
groups in ligands 8a-d and the C-2 substituent in
ligands 9a-g from Me f Et f n-Pr f n-Bu f n-amyl.
When all of these results are combined with our previous
reports,9 it appears that varying the substituent’s carbon
chain length gives variations of the ee values that depend
on the number of carbons present in the linear alkyl
substituents (e.g., an “odd-even” alternating effect).
Herein, we report the synthesis and use of five series
of chiral ligands (Schemes 1 and 2) for the enantioselec-
tive addition of diethylzinc to benzaldehyde (eq 1) at
ambient temperature.
The effect that the different free ligand conformational
populations might have on the enantioselectivity was
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262 J. Org. Chem., Vol. 70, No. 1, 2005