Analysis of an asymmetric addition with a 2:1 mixed lithium amide/n-butyllithium aggregate

Article abstract of DOI:10.1021/jo800592d

(Chemical Equation Presented) A 2:1 lithium amide/n-butyllithium aggregate 1 is investigated as an asymmetric addition template in hydrocarbon solvents. Several different chiral lithium amides were synthesized from L-valine and tested in the asymmetric addition of n-BuLi to various aldehydes. Enantiomeric excesses up to 83% were obtained in the case of the addition of n-BuLi to pivaldehyde at -116°C in pentane. ¹H and ¹³C INEPT DOSY were utilized to characterize a new trimeric complex 12 between 2 equiv of lithium amide and 1 equiv of lithium alkoxide. This mixed aggregate strongly indicates the possibility of product-induced chirality inhibition that is detrimental to the enantioselectivity of asymmetric addition reaction.

Full text of DOI:10.1021/jo800592d

Analysis of an Asymmetric Addition with a 2:1 Mixed Lithium
Amide/n-Butyllithium Aggregate
Jia Liu, Deyu Li, Chengzao Sun, and Paul G. Williard*
Department of Chemistry, Brown UniVersity, ProVidence, Rhode Island 02912
pgw@brown.edu
ReceiVed March 18, 2008
A 2:1 lithium amide/n-butyllithium aggregate 1 is investigated as an asymmetric addition template in
hydrocarbon solvents. Several different chiral lithium amides were synthesized from L-valine and tested
in the asymmetric addition of n-BuLi to various aldehydes. Enantiomeric excesses up to 83% were obtained
1
in the case of the addition of n-BuLi to pivaldehyde at -116 °C in pentane. H and 13C INEPT DOSY
were utilized to characterize a new trimeric complex 12 between 2 equiv of lithium amide and 1 equiv
of lithium alkoxide. This mixed aggregate strongly indicates the possibility of product-induced chirality
inhibition that is detrimental to the enantioselectivity of asymmetric addition reaction.
Introduction
amine ligands, which form mixed aggregates with organolithium
reagents.2g,3 The aggregates are assumed responsible for chiral
induction when organolithium reagents add to aldehydes.
We and others have observed that lithium aggregates are
strictly solvent dependent and undergo dynamic processes in
solution.3–5 For example, in ethereal solvents a variety of ligands
yield high enantioselectivities over 90% enantiomeric excess
(ee) for asymmetric butylation of benzaldehyde.3f,g,i However,
Asymmetric addition of organometallic reagents to aldehydes
allows for construction of chiral alcohols.1 Reactions involving
Grignard reagents, organozinc, and other organotransition metal
reagents have been extensively investigated by others.1,2
However, the use of alkyllithium reagent complexes in chiral
C-C bond formation is limited because of their high reactivity,
their propensity to form aggregates, and the relatively modest
enantioselectivity reported to date. Previous work in this area
has been focused on the efficiency of various polydentate chiral
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4197. (b) Granander, J.; Eriksson, J.; Hilmersson, G. Tetrahedron: Asymmetry
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10.1021/jo800592d CCC: $40.75
Published on Web 05/07/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4045–4052 4045

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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4046 J. Org. Chem. Vol. 73, No. 11, 2008

Analysis of an Asymmetric Addition
SCHEME 3. Synthesis of Chiral Amino Ether Ligand 5-8
TABLE 1. Asymmetric Alkylation of Aldehydes with n-BuLi at
-78 °C in the Presence of Chiral Lithium Amides
TABLE 2. Asymmetric Alkylation of Aldehydes with n-BuLi in
the Presence of the Chiral Ligand 8
entry
ligand/R1
R
solvent
ee (%)
entry
R
temp (°C)
eea (%)
yield (%)
1
2
3
4
5
6
7
8/TIPS
8/TIPS
8/TIPS
8/TIPS
7/TBDMS
5/methyl
6/n-butyl
Ph
Ph
toluene
pentane
toluene
pentane
pentane
pentane
pentane
45a (S)
60a (S)
48b (S)
75b (S)
54b (S)
6b (R)
1
2
3
4
5
6
7
8
9
Ph
Ph
-78
-116
-78
-116
-116
-78
-78
-116
-116
61b
76b
79b
76b
83c
59b
50c
74b
70c
96
88
60
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
t-butyl
t-butyl
t-butyl
2-furyl
2-furyl
2-furyl
2-furyl
d
-
62
65
25b (R)
d
-
a Product ee was determined by Mosher′s ester method. b Product ee
was determined by chiral GC, using a CP-Chirasil-DEX CB column.
79
d
-
a Product ee was determined by chiral GC, using a CP-Chirasil-DEX
CB column. b Aldehyde solution was injected slowly into the cold
reaction mixture via syringe pump over 1 h. c Aldehyde solution was
injected into the cold reaction mixture all at once. d Yield was not
determined.
the substituent on oxygen in ligands 5-8 affects not only
enantioselectivity, but also surprisingly the configuration of the
addition product. Ligands 7 and 8 yielded a carbinol product
with S configuration, while ligands 5 and 6 gave the carbinol
with the enantiomeric R configuration. Amino silyl ether 8
provided the best ee value (entry 4, 75% ee) among the four
ligands compared in this reaction. These results highlight that
these amino ether ligands are highly adaptable for configuration
differentiation. Although they are all derived from the same
precursor L-valinol 4, different protecting groups on the alcohol
yield totally reverse enantiomeric configuration in the products.
Because the reactions involving ligand 8 yielded the highest
ee value in hydrocarbon solvent among all the ligands 5-8,
we then turned our attention to the asymmetric additions of
n-BuLi to various aldehydes in the presence of ligand 8. These
results are summarized in Table 2.
dehyde was added to complex 1 at -78 and -116 °C, addition
all at once yielded lower ee (50% and 70% ee, respectively,
Table 2, entries 7 and 9) than slow addition of the aldehyde to
the lithium complex (59% and 74% ee respectively, Table 2,
entries 6 and 8).
We noticed solvent variation (toluene versus pentane) and
temperature change (-78 versus -116 °C) yield consistent ee
changes. However, the inconsistent observations in ee for the
addition rate led us to suspect that product-induced chirality
inhibition by an aggregate including the lithium alkoxide product
might be responsible for the unpredictable chiral inductions.7,8
In these addition reactions, enantiomeric excesses up to 83%
were observed and yields were moderate to good. The influence
of temperature is apparent that better ee is achieved by lowering
the temperature. Hence, the highest ee was obtained in the
asymmetric addition on pivaldehyde at -116 °C (Table 2, entry
5). We found ee is also sensitive to the rate of addition of
aldehyde to the preformed lithium complex 1 solution. When
0.22 mmol of pivaldehyde solution in 3 mL of pentane was
added slowly into the reaction mixture via a syringe pump at
-116 °C, the reaction yielded a low ee of 76% (Table 2, entry
4). However, when 0.22 mmol of pivaldehyde in 0.4 mL of
pentane was added all at once at the same temperature, the ee
went up to 83% (Table 2, entry 5). In contrast, when 2-fural-
We further reasoned that the asymmetric butylation is
probably not a catalytic reaction due to the following observa-
tions. Under stoichiometric conditions, i.e., preformation of the
2:1 complex 1 (6.8 equiv of n-BuLi, 5 equiv of amine 8 and 1
equiv of pivaldehyde, Table 2, entry 3) at -78 °C, all n-BuLi
is incorporated into the trimeric complex 1 with lithium amide
and 79% ee was obtained. Under nonstoichiometric conditions
(10 equiv of n-BuLi, 5 equiv of amine 8 and 1 equiv of
pivaldehyde), 2.5 equiv of trimeric complex 1 and 2.5 equiv of
uncomplexed n-butyllithium coexist in the solution and the ee
decreased to 38%. This result indicates that the racemic addition
by uncomplexed n-BuLi competes favorably with the addition
J. Org. Chem. Vol. 73, No. 11, 2008 4047

Liu et al.
SCHEME 4. Proposed Models of Asymmetric Induction
of mixed chiral complex 1 to aldehydes. Hence, a stoichiometric
quantity of the chiral complex 1 is required to achieve the
highest ee.
more significant than the previous case. Under these circum-
stances, the S enantiomer products yield a much higher ee than
the R enantiomers. Since the TIPS group is the bulkiest group
among the four and also displays the largest size difference, it
produces the highest ee among all entries (Table 2, entry 5).
NMR Investigation of Product-Induced Chirality Inhibi-
tion. 1H NMR Chemical Shift Changes. In 19974a and 20004b
we reported a series of mixed trimeric crystal structures
containing 2 equiv of lithium amide and 1 equiv of n-BuLi,
s-BuLi, t-BuLi, or lithium enolate. On the basis of these
structures, we suspect the initial addition product, i.e., the lithium
alkoxide, should also become incorporated into a similar trimeric
aggregate such as complex 12 in Figure 1.
On the basis of the published crystal structure4a and results
from the chiral butylation reactions reported in this paper, we
propose a model to explain the origin of chiral induction as
depicted in Scheme 4. After formation of the mixed aggregate
1 in hydrocarbon solvent, the carbonyl oxygen of the added
electrophilic aldehyde can coordinate to either Li2 or Li3, but
not to the more Lewis-acidic Li1 because of the extreme steric
hindrance generated by the four isopropyl groups. The crystal
structure of 1 clearly shows the pocket of Li1 is not big enough
for binding the aldehyde. Upon coordination, steric hindrance
occurs between the R group in aldehyde and either the R1 group
on oxygen or isopropyl moiety on nitrogen. If R1 is bulkier (such
as TBDMS and TIPS) than the R2-isopropyl group, model 9 is
favored; if R1 is smaller (such as Me and n-Bu group) than the
isopropyl group, model 10 is favored. In cases of ligands Li-5
and Li-6, model 10 is favored and leads to secondary alcohol
with enrichment in R configuration. In cases of Li-7 and Li-8,
aldehydes will orient the R groups toward the smaller isopropyl
moiety and the product will be mostly S enantiomer.
We performed the following NMR experiments to investigate
1
this possibility. In H NMR spectra, protons 1, 1′, 2, and 5 of
the ligand 8 and proton 9 of the addition product 11 are clearly
separable from other proton signals (see Figure 1). We utilized
1
these five peaks as the fingerprints to monitor the H NMR
variation between different species. When 1.5 equiv of n-BuLi
is added to a mixture of 1 equiv of ligand 8 and 0.5 equiv of
alcohol 11 in toluene-d8, the proton of the secondary amine in
ligand 8 and the proton of the hydroxyl group in alcohol 11 are
completely deprotonated. To verify this, we monitor the
following chemical shift: δ 4.04, 3.45, 3.15, and 2.78 ppm for
protons 1, 1′, 2, and 5 on lithium amide respectively, and δ
3.27 ppm for the proton on carbon 9 in lithium alkoxide (see
Comparing model 9 and model 10, we notice the following
differences. If R1 equals Me or n-Bu group, the size difference
between isopropyl and Me or n-Bu group is fairly small thus
yielding lower ee of the R enantiomer. On the contrary, if R1
equals TBDMS or TIPS, the size difference between the
isopropyl group and these two silyl protecting groups is much
1
Figure 1a, Table 3). Also the H NMR integration of complex
12 shows a 2:1 ratio between the lithium amide and the lithiated
4048 J. Org. Chem. Vol. 73, No. 11, 2008

Analysis of an Asymmetric Addition
1
FIGURE 1. 1H and 13C chemical shift changes: (a-e) H NMR spectra; (a′-e′) 13C NMR spectra; (a/a′) trimer 12; (b/b′) ligand 8 plus lithium
amide 13; (c/c′) ligand 8; (d/d′) lithium alkoxide 14; (e/e′) alcohol 11.
TABLE 3. 1H and 13C NMR Chemical Shifts of Components Related to Complex 12
spectra/compds
1H NMR chemical shifts
13C NMR chemical shifts
a/a′: complex 12
b/b′: amide 13 + ligand 8
4.04 (d),a 3.45 (t),a 3.27 (d),b 3.15 (br),a 2.78 (br)a
amide: 4.00 (q), 3.41 (t), 3.09 (t), 2.73 (m)
ligand: 3.60 (q), 3.55 (q), 2.79 (m), 2.29 (m)
3.58 (q), 3.52 (q), 2.75 (heptat), 2.25 (q)
3.24 (d)
82.4,b 68.5,a 67.2,a 52.1a
amide: 68.4, 67.2, 52.0
ligand: 63.2, 61.8, 46.5
63.1, 61.8, 46.5
82.0
c/c′: ligand 8
d/d′: lithium alkoxide 14
e/e′: alcohol 11
2.93 (q)
79.6
a Lithium amide, b Lithium alkoxide.
1
carbinol (see Figure S19 in the Supporting Information). This
newly formed complex has totally different chemical shifts from
the amino ether ligand 8 for protons 1, 1′, 2, and 5 (Figure 1c,
δ 3.58, 3.52, 2.75, and 2.25 ppm, respectively) and alcohol 11
for proton 9 (Figure 1e, δ 2.93 ppm). However, the H NMR
spectrum of this new complex shares very similar chemical shifts
and peak patterns to the lithium amide 13 (Figure 1b) and to
the initial addition product lithium alkoxide 14 (Figure 1d).
J. Org. Chem. Vol. 73, No. 11, 2008 4049

Liu et al.
We noted that after 0.42 equiv of n-BuLi was added to 1
equiv of amine 8 in toluene-d8 solution, ligand 8 coexists with
the newly formed lithium amide 13 seen in the 1H NMR (Figure
1b). All the proton signals of the lithium amide 13 have different
chemical shifts than the corresponding protons on the amine 8,
especially protons on carbons 1, 1′, 2, and 5 (δ 4.00, 3.41, 3.09,
and 2.73 ppm). Upon addition of 1.0 equiv of n-BuLi to the
carbinol 11 in toluene-d8 solution, the carbinol was converted
into the corresponding lithium alkoxide 14. The NMR spectrum
of the lithium alkoxide 14 is depicted in Figure 1d. The chemical
shift of the 2° carbinol proton on carbon 9 appears at δ 3.24
ppm and provides a signature of lithium alkoxide 14. With the
five peaks in complex 12 unambiguously identified, we carried
out 1H DOSY experiments to confirm the solution structure and
aggregation state of this new trimeric complex.
1H DOSY Characterization of Complex 12. DOSY is a
powerful tool to identify solution state structure of organome-
tallic complexes.11,12 DOSY can separate different species13,14
by their hydrodynamic radii15,16 and even their MW.17,18 To
avoid artifacts generated by temperature fluctuation, viscosity
change, and convection,19 we chose 1-octadecene (ODE) as the
internal reference20 for our DOSY experiments. The 1H DOSY
spectrum of mixed trimeric complex 12 with ODE in toluene-
d8 solution separates into two components in the diffusion
dimension. These are clearly identifiable in the DOSY spectrum
reproduced in Figure 2. In increasing order of diffusion
coefficient (decreasing formula weight) these are the complex
12 (C43H95Li3N2O3Si2, FW 765.2) and ODE (C18H36, FW
252.3). The 1H signals of the protons 1, 1′, 2, 3, and 5 on ligand
and proton 9 on alkoxide in complex 12 (Figure 2) have identical
diffusion coefficients. The similar diffusion behavior confirms
that the lithium alkoxide and the lithium amide are in the same
complex. Previously we have suggested a correlation between
FIGURE 2. 1H DOSY of trimeric complex 12 and ODE in toluene-d8.
enolate of tert-butyl methyl ketone,23 and solution structure of
6
1
trimeric complex 1. As we have previously noted, H DOSY
results allow us to correlate the diffusion coefficients and
formula weights of complex 12, ODE, and toluene-d8. (Table
S1 in the Supporting Information) The correlation between log
FW (formula weight) and log D (diffusion coefficient) of the
linear least-squares fit to reference points of all components in
this mixture is extremely high, r ) 0.9961 (Figure S22 in the
Supporting Information). This result establishes the complex
12 as a mixed trimeric aggregate consisting of 2 equiv of lithium
amide and 1 equiv of lithium alkoxide.
Having established the identity of compound 12, we propose
the following processes for chirality inhibition. Formation of
alkoxide containing complex 12 during the reaction competes
for the chiral lithium amide ligand with the n-BuLi containing
aggregate 1. As a consequence this competition destroys the
chiral environment of n-BuLi and is ultimately detrimental to
the enantioselective addition of n-BuLi to an electrophile. The
rate of formation of the trimeric complex between lithium amide
and lithium alkoxide is likely to be not identical for ligands
5-8 and this rate difference accounts for the inconstancy in
chiral induction for different aldehyde addition methods.
13C NMR Chemical Shift Changes. The 13C NMR experi-
ments confirm the conclusions drawn from the 1H NMR
1
diffusion coefficient and formula weight utilizing H DOSY
experiments to study dimeric and tetrameric n-BuLi,21 lithium
allylic amide aggregates22 and bis(diisopropylamino)boron
(11) (a) Cohen, Y.; Avram, L.; Frish, L. Angew. Chem., Int. Ed. 2005, 44,
520–554. (b) Dehner, A.; Kessler, H. ChemBioChem 2005, 6, 1550–1565. (c)
Valentini, M.; Ruegger, H.; Pregosin, P. S. HelV. Chim. Acta 2001, 84, 2833–
2853. (d) Johnson, C. S. Prog. Nucl. Magn. Reson. Spectrosc. 1999, 34, 203–
256.
(12) (a) He, X. Y.; Morris, J.; Noll, B. C.; Brown, S. N.; Henderson, K. W.
J. Am. Chem. Soc. 2006, 128, 13599–13610. (b) Megyes, T.; Jude, H.; Grosz,
T.; Bako, I.; Radnai, T.; Tarkanyi, G.; Palinkas, G.; Stang, P. J. J. Am. Chem.
Soc. 2005, 127, 10731–10738. (c) Corruble, A.; Davoust, D.; Desjardins, S.;
Fressigne, C.; Giessner-Prettre, C.; Harrison- Marchand, A.; Houte, H.; Lasne,
M.-C.; Maddaluno, J.; Oulyadi, H.; Valnot, J.-Y. J. Am. Chem. Soc 2002, 124,
15267–15279. (d) Pichota, A.; Pregosin, P. S.; Valentini, M.; Worle, M.; Seebach,
D. Angew. Chem., Int. Ed. 2000, 39, 153–156.
1
investigations since they display similar variations to the H
NMR spectra for the components involved in product-induced
chirality inhibition. Hence, we monitor the following 13C
chemical shift for complex 12: δ 68.5, 67.2, and 52.1 ppm for
carbons 1, 2, and 5 on lithium amide and δ 82.4 ppm for the
carbon 9 in lithium alkoxide (see Figure 1a′ and Table 3). 13C
NMR spectrum of complex 12 has totally different chemical
shifts from the amino ether ligand 8 for carbons 1, 2, and 5
(Figure 1c′, δ 63.1, 61.8, and 46.5 ppm, respectively) and
alcohol 11 for proton 9 (Figure 1e′, δ 79.6 ppm). However, the
13C NMR spectrum of this new complex shares very similar
chemical shifts to the lithium amide 13 (Figure 1b′) and to the
addition product lithium alkoxide 14 (Figure 1d′).
(13) Groves, P.; Rasmussen, M. O.; Molero, M. D.; Samain, E.; Canada,
F. J.; Driguez, H.; Jimenez-Barbero, J. Glycobiology 2004, 14, 451–456.
(14) Viel, S.; Capitani, D.; Mannina, L.; Segre, A. Biomacromolecules 2003,
4, 1843–1847.
(15) Sato, S.; Iida, J.; Suzuki, K.; Kawano, M.; Ozeki, T.; Fujita, M. Science
2006, 313, 1273–1276.
(16) Schlorer, N. E.; Cabrita, E. J.; Berger, S. Angew. Chem., Int. Ed. 2002,
41, 107–109.
(17) Nishinari, K.; Kohyama, K.; Williams, P. A.; Phillips, G. O.; Burchard,
W.; Ogino, K. Macromolecules 1991, 24, 5590–5593.
(18) Keresztes, I. Ph.D. Thesis, Brown University, 2002.
We noticed that after 0.42 equiv of n-BuLi was added to 1
equiv of amine 8 in toluene-d8 solution, ligand 8 coexists with
the lithium amide 13 seen in the 13C NMR (Figure 1b′). All the
carbon signals of the lithium amide 13 have different chemical
shifts than the corresponding carbons on the amine 8, especially
(19) (a) Sorland, G. H.; Aksnes, D. Magn. Reson. Chem. 2002, 40, S139-
S146. (b) Jerschow, A.; Mueller, N. J. Magn. Reson. 1997, 125, 372.
(20) There are three requirements for internal standards:(a) they should be
inert to the components in solution, (b) the chemical shifts of these internal
standards should not overlap with the components in solution, and (c) the internal
standards should have no or little coordinating ability to the complexes in solution.
(21) Keresztes, I.; Williard, P. G. J. Am. Chem. Soc. 2000, 122, 10228–
10229.
(22) Jacobson, M. A.; Keresztes, I.; Williard, P. G. J. Am. Chem. Soc. 2005,
127, 4965–4975.
(23) Ma, L.; Hopson, R.; Li, D.; Zhang, Y.; Williard, P. G. Organometallics
2007, 26, 5834–5839.
4050 J. Org. Chem. Vol. 73, No. 11, 2008

Analysis of an Asymmetric Addition
FIGURE 3. 13C INEPT DOSY of trimeric complex 12 and ODE in toluene-d8.
carbons on carbons 1, 2, and 5 (δ 68.4, 67.2 and 52.0 ppm).
Upon addition of 1.0 equiv of n-BuLi to the carbinol 11 in
toluene-d8 solution, the carbinol was converted into the corre-
sponding lithium alkoxide 14. The NMR spectrum of 14 is
depicted in Figure 1d′. The chemical shift of the 2° carbinol
carbon 9 appears at δ 82.0 ppm and provides a signature of the
lithium alkoxide 14. Hence, with the four peaks in complex 12
unambiguously identified and assigned, we felt confident in
carrying out 13C INEPT DOSY experiments to confirm the
solution structure of this trimeric complex.
groups on oxygen. Hence, asymmetric addition, which maxi-
mizes either R or S configuration in the product, can be carried
out without using the more expensive D-valine derivatives. We
utilized both 1H and 13C INEPT DOSY to characterize an
additional mixed trimeric complex 12 between lithium amide
and lithium alkoxide. We suggest that this complex 12 exhibits
a product-induced chirality inhibition phenomenon that is
detrimental to the asymmetric addition reaction. The chirality
inhibition we have observed is analogous but opposite in effect
to the chirality enhancement phenomena in product autoinduc-
tion. Finally, we conclude that optimization of chiral induction
correlates strongly with formation of the product containing
complex 12. These DOSY investigations of chirality inhibition
provide a new tool to analyze the versatility and complexity of
lithium aggregate chemistry.
13C INEPT DOSY Characterization of Complex 12. We
obtained 13C INEPT DOSY spectra because 13C NMR spectra
provide better resolution and a wider chemical shift range than
proton spectra and the absence of homonuclear coupling
simplifies their interpretation.24 The 13C DOSY spectrum of
complex 12 with ODE in toluene-d8 solution also separates into
two components in the diffusion dimension.25 These are clearly
identifiable in the DOSY spectrum reproduced in Figure 3. In
increasing order of diffusion coefficient (decreasing formula
weight) these are the complex 12 and ODE. The 13C signals of
oxygen or nitrogen-attached carbon 1, 2, and 5 (δ 68.5, 67.2,
and 52.1 ppm) in lithium amide and carbon 9 in lithium alkoxide
(δ 82.4 ppm) have identical diffusion coefficients. These results
Experimental Section
Reactions of asymmetric additions were preformed in flame-
dried glassware under an inert atmosphere of ultra pure Argon. All
reaction temperatures corresponded to external bath temperatures.
Solvents for these reactions were distilled from calcium hydride.
Flash column chromatography was performed by using 150 mesh
activated basic aluminum oxide. n-BuLi was titrated according to
the method of Kofron.26 1H NMR spectra were recorded at 300 or
400 MHz and 13C NMR spectra were recorded at 75 or 100 MHz
by using CDCl3 or toluene-d8 as solvents. Optical rotations were
recorded on a FTIR spectrometer. GC analyses were carried out
by using a gas chromatograph equipped with a chiral stationary-
phase column. Analyses were carried out by using helium (0.9 mL
min -1) as the carrier gas (injector 250 °C, detector 275 °C). All
separation methods for chiral material were calibrated with racemic
samples. Compound 3, 4, and 5 were synthesized according to
literature procedures.9,10
DOSY Experiments. DOSY experiments were performed on a
400 MHz spectrometer equipped with a z-axis gradient amplifier
and a z-axis gradient coil. Maximum gradient strength was 0.214
T/m. Bipolar rectangular gradients were used with total durations
of 0.5 to 3 ms. Gradient recovery delays were 0.5 to 1 ms. Diffusion
times were between 500 and 2000 ms. Individual rows of the quasi-
2-D diffusion databases were phased and baseline corrected.
Compound 5. (S)-N-Isopropyl-O-methylvalinol: 1H NMR (toluene-
d8, 300 MHz) δ 3.23-3.13 (2H, m), 3.10 (3H, m), 2.79 (1H, sept,
J ) 6.2 Hz), 2.46 (1H, dd, J ) 10.2, 5.1 Hz), 1.79 (1H, m), 0.98
1
corroborate the conclusions drawn from the H-DOSY experi-
ment that the alkoxide does indeed form a complex with the
lithium amides.
Conclusions
In this paper we have demonstrated that asymmetric n-
butylation of prochiral aldehydes is possible in hydrocarbon
solvent. The 2:1 chiral lithium amide/n-BuLi aggregate 1 serves
as the chiral addition template. Up to 83% ee has been achieved
when n-BuLi adds to pivaldehyde in pentane at -116 °C. Our
results suggest that the protecting group on oxygen in a ligand
is very important to control not only enantiomeric excess but
also configuration of products since both R and S carbinol have
been obtained by using L-valine derived ligands with different
(24) (a) Li, D.; Hopson, R.; Li, W.; Liu, J.; Williard, P. G. Org. Lett. 2008,
10, 909–911. (b) Schlorer, N. E.; Cabrita, E. J.; Berger, S. Angew. Chem., Int.
Ed. 2002, 41, 107–109. (c) Kapur, G. S.; Findeisen, M.; Berger, S. Fuel 2000,
79, 1347–1351. (d) Wu, D. H.; Chen, A. D.; Johnson, C. S. J. Magn. Reson.
Ser. A 1996, 123, 215–218.
(25) Toluene-d8 has no proton thus cannot be detected by the 13C INEPT
type DOSY experiment.
(26) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879–1880.
J. Org. Chem. Vol. 73, No. 11, 2008 4051

Liu et al.
(6H, dd, J ) 6.2, 2.7 Hz), 0.94 (6H, d, J ) 6.9 Hz); 13C NMR
(toluene-d8, 75 MHz) δ 73.4, 59.8, 58.6, 46.6, 30.1, 24.0, 23.8,
19.2, 18.8.
Synthesis of Compound 8. To a solution of 4 (2.9 g, 20 mmol)
and triethylamine (5.58 mL, 40 mmol) in 60 mL of CH2Cl2 was
added at 0 °C triisopropylsilyl triflate (6.93 mL, 25 mmol). The
mixture was stirred and allowed to warm to room temperature in
4 h. The reaction was quenched with 20 mL of 2 M NaHCO3. After
3 × 20 mL ether washes of the aqueous layer, the organic layers
were combined, washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure. The crude yellow liquid was
purified by flash column chromatography (aluminum oxide, 150
mesh, basic, activated) followed by distillation to give colorless
oil (3.2 g, 53.1%, bp 87 °C/2.5 mmHg). 1H NMR (300 MHz,
CDCl3) δ 3.70 (dd, 1H, J ) 9.9, 5.2 Hz), 3.60 (dd, 1H, J ) 9.9,
5.5 Hz), 2.85 (heptat, 1H, J ) 6.2 Hz), 2.39 (q, 1H, J ) 5.2 Hz),
1.83 (m, 1H), 1.44-1.02 (m, 27H), 0.93 (d, 3H, J ) 6.9 Hz), 0.92
(d, 3H, J ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 63.1, 61.7,
46.7, 29.3, 23.7, 23.6, 22.1, 18.9, 18.7, 17.5, 13.9, 12.2, 11.9, 11.6;
IR (KBr) 2954, 2867, 2722, 2631, 2362, 1464, 1382, 1333, 1249,
1174, 1099, 1067, 1011, 883, 772, 730, 683 cm-1; optical rotation
[R]24.6D -8.9 (c 1.0, EtOH); HRMS (FAB) MH+, found 302.2875,
C17H39NOSi calcd 302.2879.
Synthesis of Compound 6. To a suspension of sodium hydride
(0.3 g, 60% dispersion in mineral oil, 7.5 mmol) in THF (40 mL)
was added compound 4 in THF (11 mL) dropwise (0.72 g, 5 mmol)
at room temperature and the mixture was heated to reflux overnight.
The mixture was cooled to 0 °C and n-butyl bromide (0.83 g, 6 mmol
in THF 10 mL) was added dropwise. The reaction mixture was heated
to reflux for 2 h. Saturated aqueous sodium chloride was slowly added
to the reaction mixture and the organic layer was separated. The
aqueous layer was extracted with dichloromethane twice. The com-
bined organic layer was dried over sodium sulfate and concentrated
under vacuum. The residue was purified by flash column chroma-
tography (aluminum oxide, 150 mesh, basic, activated) followed
by distillation to yield colorless oil (0.66 g, 66%, bp 104-105 °C/
1
20 mmHg). H NMR (300 MHz, CDCl3) δ 3.43-3.38 (m, 3H),
3.31 (dd, 1H, J ) 9.4, 5.9 Hz), 2.86 (hept, 1H, J ) 6.2 Hz), 2.54
(q, 1H, J ) 5.2 Hz), 1.84 (m, 1H), 1.56 (tt, 2H, J ) 6.5 Hz), 1.37
(m, 2H), 1.05 (d, 6H, J ) 6.1 Hz), 1.04 (d, 6H, J ) 6.1 Hz),
0.95-0.90 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 71.4, 71.0, 59.6,
46.6, 31.8, 29.4, 23.7, 23.6, 19.4, 18.6, 18.6, 13.9; IR (KBr) 3330,
3178, 2962, 2729, 2609, 2365, 2336, 2103, 1464, 1408, 1380, 1334,
1304, 1249, 1174, 1105, 1050, 999, 975, 919, 899, 852, 736, 646
Determination of the Absolute Configuration of Secondary
Alcohols. (S)-1-phenyl-1-pentanol: GC retention time on chiral
stationary-phase at 130 °C, 29.8 (S) and 31.2 (R) min, 76% ee.
Absolute stereochemistry was assigned in accord with the published
value of GC retention time.3i
cm-1; optical rotation [R]25.6 -5.4 (c 1.0, EtOH); HRMS (FAB)
D
(S)-2,2-Dimethyl-3-heptanol: [R]24 -16.8 (c 0.25, cyclopen-
D
MH+, found 202.2180, C12H27NO calcd 202.2171.
tane), 83% ee. Absolute stereochemistry was assigned in accord
Synthesis of Compound 7. tert-Butyldimethylsilyl chloride (1.24
g, 8.2mmol) was added to an ice-cooled solution of 4 (0.72 g, 5
mmol) and imidazole (0.89 g, 13 mmol) in dichloromethane (40
mL). The reaction mixture was stirred and allowed to warm to room
temperature. The reaction was quenched with NaHCO3 (10 mL)
and the organic layer was separated. The aqueous layer was
extracted with dichloromethane. The combined organic layer was
dried over sodium sulfate and concentrated under vacuum. The
residue was purified by flash column chromatography (aluminum
oxide, 150 mesh, basic, activated) followed by distillation to give
with the published value of optical rotation.27
(S)-R-Butyl-2-furanmethanol: [R]24D -10.4 (c 1.00, CHCl3), 74%
ee. Absolute stereochemistry was assigned in accord with the
published value of optical rotation.28
Acknowledgment. This work is supported through NSF
Grant 0718275 and in part by the National Institutes of Health
Grant GM-35982.
1
Supporting Information Available: H NMR, 13C NMR,
1
and IR spectra of ligands 5-8, 1H NMR and 13C NMR spectra
colorless oil (0.62 g, 47.9%, bp 79-80 °C/2.2 mmHg). H NMR
1
(300 MHz, CDCl3) δ 3.60 (dd, 1H, J ) 10.0, 5.3 Hz), 3.51 (dd,
1H, J ) 10.0, 5.3 Hz), 2.83 (m, 1H), 2.38 (m, 1H), 1.81 (m, 1H),
1.05 (d, 3H, J ) 6.1 Hz), 1.03 (d, 3H, J ) 6.1 Hz), 0.88-0.93 (m,
15H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 62.7, 61.4, 46.6,
29.3, 25.9, 23.7, 23.5, 18.9, 18.6, 18.2, -5.5; IR (KBr) 3330, 3175,
2955, 2858, 2738, 2710, 2635, 2363, 2337, 1922, 1749, 1651, 1468,
1382, 1364, 1334, 1254, 1218, 1174, 1094, 1007, 979, 956, 939,
908, 835, 777, 730, 671, 611 cm-1; optical rotation [R]24.2D -11.4
(c 1.0, EtOH); HRMS (FAB) MH+, found 260.2418, C14H33NOSi
calcd 260.2410.
and GC analysis of the three addition products, and H NMR,
13C NMR, 1H DOSY, and 13C INEPT DOSY spectra of complex
12. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800592D
(27) Yamaguchi, S.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1972, 37,
3174–3176.
(28) Kametani, T.; Tsubuki, M.; Tatsuzaki, Y.; Honda, T. J. Chem. Soc.,
Perkin Trans. 1 1990, 639–646.
4052 J. Org. Chem. Vol. 73, No. 11, 2008