Liu et al.
SCHEME 1. Mixed Trimeric Complex 1 between 2 equiv of
SCHEME 2. Synthesis of Amino Alcohol 4
Lithium Amide and 1 equiv of n-BuLi
yield product 3.9 The N-isopropyl valine 3 was then reduced to
the desired amino alcohol 4 with lithium aluminum hydride as
depicted in Scheme 2.10
From amino alcohol 4, two paths were developed to synthe-
size the chiral ligands (Scheme 3). In the first route, the amino
alcohol 4 was deprotonated by being refluxed with sodium
hydride in THF for 18 h, before it reacted with methyl iodide
or n-butyl bromide. The reflux was necessary to avoid N-
alkylation byproducts. The resulting 5 and 6 were easily purified
by flash chromatography followed by distillation.
In the second synthetic route (Scheme 3), ligand 7 was
prepared from amino alcohol 4 by using tert-butyldi-
methylsilyl chloride and imidazole. Ligand 8 was synthesized
in a similar route with triisopropylsilyl triflate as a silylating
reagent and triethylamine as a base.
Asymmetric Addition of n-BuLi to Aldehydes. The amino
ethers 5-8 were then utilized as chiral ligands in the addition
reaction of n-BuLi to benzaldehyde and pivaldehyde to evaluate
their ability for chiral induction. We surveyed all ligands
individually in either toluene or pentane. To a solution of 1
equiv of each pure ligand at -78 °C, 1.45 equiv of n-BuLi was
added dropwise to form the complex 1. The reaction mixture
was warmed to 0 °C for 20 min before it was cooled again to
-78 °C. After the solution equilibrated for 30 min, a solution
of aldehyde was added either all at once or slowly via a syringe
pump. The reaction was quenched 1 h after addition of aldehyde
with methanol and saturated aqueous ammonium chloride.
Purified product alcohol was analyzed by chiral stationary-phase
GC. The results are summarized in Table 1.
much less is known about their chiral induction potential in
hydrocarbon solvent. Hence, we analyzed the asymmetric
induction potential of lithium aggregate in the absence of
coordinating solvent.
In 1997 we reported a mixed trimeric complex 1 (Scheme 1)
containing 1 equiv of n-butyllithium (n-BuLi) and 2 equiv of
lithium amide.4a Crystallization4a combined with diffusion-
ordered NMR spectroscopy (DOSY) studies6 indicated that it
is the major species in hydrocarbon solvent. This prompted us
to explore the chiral induction potential of the mixed trimers
with various lithium amides derived from L-valine. These natural
amino acid derivatives have been shown to form a 1:1 mixed
dimer with n-BuLi in ethereal solvent and the enantioselective
addition reactions have been intensively studied.3f,g,i In contrast,
little attention has been devoted to the 2:1 trimer in hydrocarbon
solvent and its capability for asymmetric induction. In this paper
we wish to report results of enantioselective addition using the
trimeric aggregate 1 as the asymmetric template. We also
demonstrate a product-induced chirality inhibition phenom-
enon3i,7,8 by DOSY experiments.
Results and Discussion
Synthesis of Chiral Amino Ether Ligands. The synthetic
route we adopted to prepare chiral amino ether ligands started
from enantiomerically pure L-valine 2 (Scheme 2). The amino
group condensed with acetone to afford the corresponding imine,
and subsequently reduced with sodium cyanoborohydride to
The chiral lithium amide ligands effected moderate to good
enantioselectivities. Comparison of entry 1 to 2 and entry 3 to
4 showed that the enantioselectivity is generally lower in toluene.
Therefore, the remaining experiments were carried out in
pentane. Entries 4, 5, 6, and 7 illustrated that relative size of
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