Composition and structure of activated complexes in stereoselective deprotonation of cyclohexene oxide by a mixed dimer of chiral lithium amide and lithiated imidazole

Article abstract of DOI:10.1016/j.tetasy.2004.03.042

Stereoselective deprotonation of cyclohexene oxide, using a mixed dimer built of the chiral lithium amide, lithium (1R,2S)-N-methyl-1-phenyl-2- pyrrolidinyl-propanamide, and 2-lithio-1-methylimidazole, has been studied. The composition of the rate limiting activated complex was determined by kinetics to be built from one mixed dimer molecule and one epoxide molecule. Based on this knowledge computational chemistry has been applied to gain insight into possible structures of the activated complexes.

Full text of DOI:10.1016/j.tetasy.2004.03.042

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1607–1613
Composition and structure of activated complexes in stereoselective
deprotonation of cyclohexene oxide by a mixed dimer of chiral
lithium amide and lithiated imidazole
Daniel Pettersen, Peter Din ꢀe r, Mohamed Amedjkouh and Per Ahlberg*
Department of Chemistry, G €o teborg University, SE-41296 G €o teborg, Sweden
Received 8 March 2004; accepted 29 March 2004
Available online
Abstract—Stereoselective deprotonation of cyclohexene oxide, using a mixed dimer built of the chiral lithium amide, lithium
(1R,2S)-N-methyl-1-phenyl-2-pyrrolidinyl-propanamide, and 2-lithio-1-methylimidazole, has been studied. The composition of the
rate limiting activated complex was determined by kinetics to be built from one mixed dimer molecule and one epoxide molecule.
Based on this knowledge computational chemistry has been applied to gain insight into possible structures of the activated com-
plexes.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
O
R*NLi
BH
Chiral lithium amides have been developed for enan-
tioselective deprotonation reactions of, for example,
2
1
epoxides and ketones. Such reactions are synthetically
important since the chiral products obtained are useful
intermediates in the organic synthesis, for example, of
OH
2
biologically active compounds. The chiral lithium
R*NH
BLi
amides are often applied in stoichiometric amounts or in
excess. Alternatively, there have also been a number of
attempts to run the enantioselective deprotonation
reactions, for example, of epoxides under catalytic
(
S)-4
Scheme 1.
2–4
conditions.
The chiral lithium amide (R*NLi) has
thermodynamic basicity, is required. In our search for
such bases, we used 1-methylimidazole 1 as a bulk base
precursor. This azole underwent carbon deprotona-
tion at the C-2-position by n-BuLi to yield the carbenoid
compound 2-lithio-1-methylimidazole Li-1 (Scheme
been used in sub-stoichiometric amounts in the presence
of a bulk base (BLi) working as a chiral lithium amide-
regenerating reagent, in order to obtain a catalytic cycle
4;5
(
Scheme 1). However, nonenantioselective deprotona-
5;6
tion by the bulk base yields a racemic product that
competes with that of the chiral base, resulting in lower
enantioselectivity than in the stoichiometric reaction
with chiral lithium amide.
2).
Li
n-BuLi
THF
N
N
N
N
In order to improve the degree of enantioselectivity in
catalytic deprotonations, access to bulk bases with lower
kinetic basicity than, for example, lithium diisopropyl
lithium amide LDA, but with comparable or higher
1
Li-1
Scheme 2.
The deprotonating ability of the base Li-1 was studied
using cyclohexene oxide 2 as substrate. In contrast to
LDA, Li-1 did not yield any deprotonation of 2. This is
*
Corresponding author. Tel.: +46-31-772-2899; fax: +46-31-772-2908;
e-mail: per.ahlberg@chem.gu.se
0
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.042

1608
D. Pettersen et al. / Tetrahedron: Asymmetry 15 (2004) 1607–1613
presumably due to the fact that proton transfer to car-
bon is usually slower than that to a more electronegative
atom such as nitrogen. This result indicates that Li-1
should be a useful bulk base in catalytic asymmetric
deprotonation.
using mixtures of isotopically labeled Li-3 and Li-1, it
was shown that mixed dimer (heterodimer) 5, composed
of one molecule of Li-1 and one molecule of Li-3, is
formed. In solutions made from equimolar amounts of
Li-1 and Li-3 in THF, heterodimer 5 was exclusively
formed at the expense of homoaggregates (Scheme 3).
Indeed as expected, it was found that when using Li-1 as
a bulk base instead of LDA together with the chiral base
Li-3 as a catalyst, deprotonation of 2 produced chiral
allylic lithium alkoxide (S)-Li-4 with the same repro-
ducible stereoselectivity (93% ee) as the deprotonation in
In order to clarify the role of the mixed dimer in the
deprotonation reaction, we performed kinetic and
computational studies of the composition and structures
of the rate-limiting activated complexes involved in the
reaction.
4
the absence of the bulk base.
Interestingly, when running the deprotonation using
equimolar amounts of chiral base Li-3 and bulk base
Li-1 an increase in stereoselectivity (96% ee) was observed.
Apparently the bulk base plays a more intricate role
than just regenerating the chiral base from the chiral
The asymmetric deprotonation of cyclohexene oxide 2
by mixed dimer 5 was carried out in THF at 20.0 °C
using different concentrations of 2 and 5. The concen-
trations of product 4 over time were determined using a
calibrated quench-extraction-GC procedure. The reac-
tions were followed close to completion; a plot of the
concentration of the product versus time turned out to
be close to linear for a large fraction of the reaction.
This indicated that the reaction products diamine
(1R,2S)-N-methyl-1-phenyl-2-pyrrolidinyl-propanamide
3 and 1-methylimidazole 1 modify the rates of the
reactions. The enantiomeric excess of the (S)-allylic
alcohol was found not to change significantly (ꢀ0.2%)
during the reaction. In order to avoid interference of
reaction products, initial rates were determined using
data for only ca. 0.5% conversion (Table 1).
4
diamine formed upon deprotonation of the epoxide.
We herein report the results of an investigation into
molecular composition of the deprotonation activated
complexes. Kinetics have been used to determine the
composition of the rate limiting activated complexes and
based on this knowledge, computational chemistry has
been applied to calculate structures of the activated
complexes.
2
. Results and discussion
Table 1. Initial rates obtained from 0.5% reaction in runs with dif-
ferent concentrations of reagents and additives in THF at 20.0 °C
Kinetics can tell us about the molecular composition of
activated complexes in reactions through experimentally
determined reaction orders, if the molecular composi-
Run [2]/
mM
[5]/mM
[(Li-3)
a
mM
2
]/ [1]/mM [3]/mM
(d[4]/dt)/
10 M s
7
7
ꢁ1
tion of the reagents in the initial state is known.
5
0
100
100
11.5
11.4
Lithium amides are strong dipoles, which makes them
8
50
50
00
a
prone to aggregate. The aggregate composition of
homochiral lithium amide Li-3 has previously been
100
51.3
1
50
50
11.8
11.8
18.1
18.7
22.4
23.2
23.1
23.0
13.5
58.5
6
13
100
100
investigated using Li and C labeled chiral lithium
5
75
75
amide and multinuclear NMR spectroscopy. The re-
sults show that Li-3 in tetrahydrofuran (THF) is present
1
1
1
1
1
1
1
1
00
00
00
00
00
00
00
00
100
100
100
100
100
100
2
as homodimer (Li-3) in the initial state (Scheme 3).
100
100
a
100
100
103
102
a
N
N
N
N
100
1
1
2
2
2
00
00
00
00
00
200
200
100
100
41.0
46.9
47.4
48.9
Li
Li
N
N
Li
Li
N
5
NLi
N
N
a
100
195
a
Initial rates taken from Ref. 9.
Li-3
(Li-3)
2
Scheme 3.
The reaction orders with respect to the epoxide 2 and the
mixed dimer 5 were obtained from the plots of log (ini-
tial rate) versus log (concentration) as shown in Figures
1 and 2.
The rate-limiting activated complex in the deprotona-
tion reaction of epoxide 2 by (Li-3) has been shown to
2
be built from one molecule of 2 and one molecule of (Li-
7
The gradients give the experimental reaction orders and
were determined to be 1.03 and 0.94 for 2 and 5,
;9
3
)
2
rather than a monomer of Li-3. Furthermore, by

D. Pettersen et al. / Tetrahedron: Asymmetry 15 (2004) 1607–1613
1609
-
-
-
-
-
-
-
-
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
ing to (R)- and (S)-products have been calculated. Ini-
tially, the PM3 level of theory was used, since PM3
is known to give geometries of organolithium com-
10–14
pounds similar to those obtained from experiment and
15;16
high level theory.
The most stable structures were
optimized using density functional theory (DFT). In the
calculations of the deprotonation activating complex
involving heterodimer 5, a syn-b-elimination mechanism
1
7;18
was assumed.
Recently, experimental evidence for
19
this mechanism has been obtained. Calculations of
5
heterodimer 5 itself have previously been reported.
-
6
-
1.4
-1.2
-1
-0.8
-0.6
Log[2]
In the transition states for deprotonation of 2, one
lithium atom (Li1) from the mixed dimer coordinates to
the epoxide oxygen (O1), while the amide nitrogen (N1)
abstracts the b-proton (Scheme 4).
Figure 1. Plot of log (d[4]/dt) versus log [2] is shown and the reaction
order with respect to 2 obtained from the gradient.
-
-
-
-
-
-
-
-
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
N
3
N3
Li
2
Li
Li
2
N
3
C
N
2
N1
N1
N2
C3
Li
1
1
N
H
1
H1
O
1
O
1
C2
C2
(
S)-TSa
(S)-TSb
-
6
-
1.4
-1.2
-1
Log[5]
-0.8
-0.6
Scheme 4.
Figure 2. Plot of log (d[4]/dt) versus log [5] is shown and the reaction
order with respect to 5 obtained from the gradient.
The most stable unsolvated activated complexes, leading
to (R)- and (S)-product at the B3LYP/6-31 þ G(d)//PM3
level of theory, were further optimized at B3LYP/6-
20;21
31G(d)//B3LYP/6-31G(d) level of theory.
The most
respectively, that is, the reaction is first-order both in the
case of the epoxide 2 and mixed dimer 5. This shows that
the deprotonation takes place via a transition state built
from one molecule of epoxide 2 and one molecule of
heterodimer 5. This is in contrast to the results of the
stable activated complexes, (R)-TSa and (S)-TSa, have
an (R)-configuration on the amide nitrogen (N1) while
the oxygen-coordinated lithium atom (Li1) was also
coordinated to the carbon (C3) in the imidazole ring
(Fig. 3).
kinetics in THF for the deprotonation of 2 by (Li-3) in
2
the absence of Li-1, which has previously shown that
the transition state is composed of one molecule of
homodimer (Li-3) and one molecule of epoxide 2. This
2
All distances in the reaction center six-membered rings
of the activated complexes (R)-TSa and (S)-TSa are
similar (Fig. 3). The C1–O1 bond of the epoxide part
9
ꢁ
difference in transition state composition is concluded to
be the reason for the change of stereoselectivity. The
difference between the stereoselectivities observed for the
reactions run under stoichiometric conditions (96% ee)
and catalytic conditions (93% ee) could be due to dif-
ferential solvation by the lithium methylimidazole of the
diastereoisomeric activated complexes. This acquired
knowledge of the molecular composition of the acti-
vated complexes was the starting point for a computa-
tional investigation of possible activated complex
structures with the results presented below.
was substantially broken (1.97 A), while the N1–Li1
coordination in the activated complexes were elongated
ꢁ
(2.14 A) when compared to the Li1–N1 coordination
ꢁ
bond in the mixed dimer itself (1.91 A). Geometrical
differences between the diastereoisomeric activated
complexes (R)-TSa and (S)-TSa were found in the ori-
entation of the phenyl group and of the methyl group
attached to the amide nitrogen (N1). In (R)-Tsa, the
phenyl group is located on the same side of the mixed
dimer as the cyclohexene oxide moiety while the N-me-
thyl group is on the opposite side. In (S)-TSa, the N-
methyl group is located on the same side as the cyclo-
hexene oxide moiety while the phenyl group is on the
opposite side.
3
. Computational studies of the activated complexes
The potential energy surfaces for the stereoselective
deprotonations were explored computationally. The rate
limiting activated complexes were identified as the
deprotonation activated complexes. The geometries and
energies of possible isomeric activated complexes lead-
The next most stable activated complexes at the B3LYP/
6-31 þ G(d)//PM3 level of theory, (R)-TSb, and (S)-TSb,
were also further optimized at B3LYP/6-31G(d) level of
theory. In these activated complexes, the oxygen-coor-
dinated lithium coordinates to the nitrogen (N2) in the

1610
D. Pettersen et al. / Tetrahedron: Asymmetry 15 (2004) 1607–1613
ꢁ1
Figure 3. Optimized unsolvated activated complexes at B3LYP/6-31G(d) level of theory. Relative energies in kcal mol are shown in parentheses.
Hydrogens are omitted for clarity.
ꢁ
1
imidazole ring rather than C3. The different orientation
of the imidazole ring in activated complexes, (R)-TSb,
and (S)-TSb, induce geometrical changes when com-
pared to activated complexes (R)-TSa and (S)-TSa. For
example, the proton in the transfer is more shifted from
the carbon in the cyclohexene oxide part toward the
0.69 kcal mol ) when compared to (S)-TSa and (R)-
TSa, respectively.
The potential energy difference between the two most
stable activated complexes at the B3LYP/6-31G(d) level
of theory corresponds to an enantiomeric excess of the
(S)-enantiomer of 51% at 298 K (Table 2). The calcu-
ꢁ
ꢁ
amide nitrogen (C2–H1: 1.33 A, N1–H1: 1.46 A in (R)-
TSb and (S)-TSb), than in (R)-TSa and (S)-TSa (C2–
lated Gibbs free energy difference between the two most
ꢁ1
ꢁ
ꢁ
H1: 1.30 A; N1–H1: 1.50 A, respectively); the coordi-
nation of lithium (Li1) to the amide nitrogen (N1) is also
stable activated complexes was 0.063 kcal mol
at
298 K, which corresponds to a calculated enantiomeric
excess of the (S)-enantiomer of only 5%. Thus, the ob-
served favored enantiomer is also the one that is pre-
dicted by the calculations although the prediction is far
from being quantitative.
ꢁ
slightly longer (0.05–0.07 A), and the Li1–Li2 distance is
ꢁ
increased (0.18–0.20 A). At the B3LYP/6-31G(d) level of
theory, the difference in potential energy between (S)-
TSa and (R)-TSa was 0.66 kcal mol favoring the for-
mation of (S)-product. The changed orientation of the
imidazole rings in (S)-TSb and (R)-TSb led to small
increases of the activation energies (0.4 and
ꢁ
1
Activated complexes, with the coordination between the
lithium and the nitrogen in the pyrrolidine ring broken,

D. Pettersen et al. / Tetrahedron: Asymmetry 15 (2004) 1607–1613
1611
ꢁ
1
Table 2. Calculated energy differences in kcal mol between the most
stable diastereoisomeric activated complexes at the B3LYP/6-31G(d),
together with calculated and experimental enantiomeric excesses
ences in Li1–C3 and Li1–N2 bond lengths due to the
orientation of the imidazole ring (Fig. 4). In (R)-
TSÆTHF, the oxygen-coordinated lithium (Li1) is coor-
dinated to a carbon (C3) in the imidazole ring, while in
a
b
c
d
Solvent
DECalcd
DGCalcd
DGExp
EeCalcd
EeExp
(
S)-TSÆTHF, the lithium (Li1) is coordinated to the
nitrogen (N2). The lithium coordination to the epoxide
None
THF
None
THF
THF
0.66
0.73
51(S)
56(S)
5(S)
ꢁ
oxygen (O1) is also longer (0.04–0.05 A) than in the
0.063
0.51
41(S)
unsolvated activated complexes due to the THF solva-
tion.
2.30
96
a
Potential energy difference between the two most stable TSs.
Calculated Gibbs free energy differences between the two most stable
TSs at 298 K.
b
The potential energy difference between the activated
complexes (R)-TSÆTHF and (S)-TSÆTHF was
0.73 kcal mol in favor of forming (S)-products at the
c
ꢁ1
Experimental Gibbs free energy difference at 293 K calculated from
the experimental ee.
B3LYP/6-31G(d) level of theory. The potential energy
difference between the most stable activated complexes
corresponds to an enantiomeric excess of 56% at 298 K.
The calculated Gibbs free energy difference between the
d
Enantiomeric excesses calculated from the potential energy difference
between the two most stable TSs at 298 K.
ꢁ
1
two most stable activated complexes was 0.51 kcal mol ,
which corresponds to a calculated enantiomeric excess of
the (S)-enantiomer of 41% (Table 2).
were also investigated but were found to be 14–
ꢁ
1
2
4 kcal mol less stable than (R)-TSa at the B3LYP/6-
1 þ G(d)//PM3 level of theory and therefore not opti-
3
mized further.
The energy difference between the geometry optimized
activated complexes at the B3LYP/6-31G(d) predicts the
Monosolvation by THF of the lithium coordinating the
epoxide oxygen in the activated complexes leads to
(
S)-allylic lithium alkoxide as the main product in the
deprotonation of cyclohexene oxide. The theoretically
derived enantiomeric excess was 51% for the unsolvated
and 55% for the THF solvated activated complexes.
Thus, the predicted values are lower than the experi-
mentally observed ee of 96%.
ꢁ
1
stabilization by 1.7–4.9 kcal mol at the PM3 level of
theory. Monosolvation of the second lithium (Li2),
which coordinates the nitrogen in the pyrrolidine ring in
the activated complex of the mixed dimer, results in
destabilization at the PM3 level of theory of the acti-
ꢁ
1
vated complexes by a few kcal mol . Therefore, further
solvation at this position was not considered.
The two most stable monosolvated activated complexes
found at the B3LYP/6-31 þ G(d)//PM3 level of theory
were further optimized at the B3LYP/6-31G(d) level of
theory. A major structural difference caused by
THF-solvation is that the bonds between lithium (Li1)
4. Conclusion
The composition of the rate-limiting activated complex
in the deprotonation of cyclohexene oxide by mixed
dimer 5 has been determined using kinetics. Our results
show that diastereoisomeric activated complexes are not
only built from one molecule of the chiral lithium amide
and one molecule of epoxide, but that the transition
state also contains one molecule of the bulk base. Cal-
culations correctly predicted the (S)-allylic alcohol as
the major product in accordance with the experimental
22–24
and amide nitrogen (N1) are broken in (R)-TSÆTHF
ꢁ
ꢁ
(
unsolvated counter parts (R)-TSa and (S)-TSa (2.14 A).
3.79 A) and (S)-TSÆTHF (3.72 A), compared to their
ꢁ
The major differences between the activated complexes
(
R)-TSÆTHF and (S)-TSÆTHF comes from the differ-
ꢁ1
Figure 4. Optimized THF-solvated activated complexes at B3LYP/6-31G(d) level of theory. Relative energies in kcal mol are shown in parentheses.
Hydrogens are omitted for clarity.

1612
D. Pettersen et al. / Tetrahedron: Asymmetry 15 (2004) 1607–1613
result. These findings have implications for the use of
mixed dimers in design of stereoselective deprotonation
systems.
(50 lL, 0.1 mmol, 2 M in THF) were dissolved in THF
(796 lL) in a reaction vessel inside a glove box, trans-
ferred out of the glove box and n-butyllithium (82.0 lL,
0
.2 mmol, 2.44 M in hexanes) then added under a
nitrogen atmosphere. The yellow reaction solution was
allowed to equilibrate at 20.00 ꢀ 0.05 °C for 10 min in a
thermostat. The reaction was started by the addition of
cyclohexene oxide 2 (50 lL, 0.1 mmol, 2.0 M) with
samples (50 lL) withdrawn at approximately 3 min
intervals from the reaction vessel and quenched in
hydrochloric acid solution (100 lL, 0.6 M saturated with
sodium chloride). Compounds 2 and 4 were extracted
with carbon tetrachloride (500 L) containing the stan-
dard 1-hexanol (3.40 mM). The liquid phases were sep-
arated by centrifugation and the organic phase
transferred to a vial and analyzed by capillary gas
chromatography.
5
. Experimental
5
.1. General
Reaction vessels and syringes dried in a vacuum oven
(
50 °C) overnight. Transfers of reagents were performed
with gas-tight syringes in nitrogen atmosphere. THF
was distilled from sodium benzophenone ketyl in a
nitrogen atmosphere and stored over molecular sieves
ꢁ
(
4 A) in septum sealed vials in a glove box (Mecaplex
GB 80 equipped with a gas purification system that re-
moves oxygen and water). A stock solution (2.0 M) of
cyclohexene oxide (distilled from calcium hydride) in
THF was prepared inside the glove box. 1-Hexanol was
used as a standard in the GC-analysis; a stock solution
(3.40 mM) of 1-hexanol (distilled from calcium hydride)
in carbon tetrachloride (distilled from calcium chloride)
was prepared. The concentration of n-butyllithium was
9
determined by a double Gilman titration.
The quantitative transfer of 2 and 4 from the aqueous
phase to the carbon tetrachloride phase during the
workup was determined as follows: solutions of 2 and 4
in THF with compositions similar to those in the kinetic
experiments were prepared. Samples (50 lL) were with-
drawn and added to solutions of carbon tetrachloride
(500 lL) containing 1-hexanol (3.16 mM). Other sam-
ples (50 lL) of solutions of 2 and 4 were added to
solutions of hydrochloric acid (100 lL, 0.6 M saturated
with sodium chloride). The latter mixtures were
extracted with solutions of carbon tetrachloride (500 lL)
containing 1-hexanol (3.16 mM). After separation by
centrifugation, the organic layers were transferred to
vials. The samples from the two types of preparations
were analyzed with capillary gas chromatography. The
concentration ratios of epoxide 2 and allylic alcohol 4 to
1-hexanol determined for the two types of preparations
were found to be within 0.5% of the average value,
respectively.
5
.2. Gas chromatography analysis
Gas chromatography analyses were performed on a
Varian 3400 chromatograph equipped with an 8200 Cx
auto sampler and a flame ionization detector (FID). For
the separation, an achiral DBWX-30W column (30 m,
0
.25 lm) from Varian Inc. was used with hydrogen as
ꢁ
1
the carrier gas (2 mL min ). Reaction samples (1.0 lL)
were introduced onto the column via a split injector
ꢁ
1
(
split flow 15 mL min ) and the components separated
using a temperature program. Initially the temperature
was held at 80 °C for 2 min and then for a further 2 min
increased to 120 °C. The injector temperature was
The concentration of 4 was measured for about the first
0.5% of conversion of 2. Initial rates were usually
reproduced within 2% of the average values, respec-
tively.
2
25 °C while the detector was held at 250 °C.
Gas chromatography response factors for 2 and 4 were
determined, using 1-hexanol as a reference, to be
1
4
.01and 0.85, respectively. The enantiomeric excesses of
were measured using a Chrompack Chirasil-CB Dex
5.4. Computational details
(
4
30 m, 0.25) at 95 °C. t
R
(S)-4 ¼ 6.85 min, t
R
(R)-
All activated complexes were optimized at the PM3 level
All activated
10–14
¼ 7.30 min.
of theory using the option HHon.
complexes were verified as first order saddle points on
the potential energy surface (PES) by using the fre-
quencies obtained from the force constant matrix and by
visualization of the imaginary frequency at the PM3.
The most stable activated complexes at the B3LYP/6-
31 þ G(d)//PM3 level of theory were further optimized
The reproducibility of the GC-analyses procedure was
investigated by analysis of a reaction sample of the (S)-
and (R)-allylic alcohol [93% ee of (S)]. Seventeen injec-
tions gave an average value of 93.3% with 2r equal to
0
.2%. The enantiomeric excess of the (S)-allylic alcohol
2
2–24
was monitored during the conversion of the epoxide
while the ee was found to be consistently within exper-
imental error (95.8 ꢀ 0.3%).
at the B3LYP/6-31G(d) level of theory.
All DFT
25
calculations were performed by GAUSSIAN 98
.
The most stable activated complexes [three leading to
the (R)- and three leading to (S)-product] at the B3LYP/
6-31 þ G(d)//PM3 level of theory were then further
geometrically optimized at B3LYP/6-31G, followed by
geometry optimization at the B3LYP/6-31G(d) level of
theory. Different conformers of the activated complexes
5
.3. Typical kinetic procedure
Amine (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinyl-prop-
9
anamine (21.8 lL, 0.1 mmol) and 1-methylimidazole

D. Pettersen et al. / Tetrahedron: Asymmetry 15 (2004) 1607–1613
1613
were investigated by structure modifications. These
modifications were performed by altering the orienta-
tion of the imidazole ring, having either an (R)- or (S)-
configuration on the abstracting amide nitrogen, by
rotation of the phenyl group, by breakage of the coor-
dination between the lithium and the nitrogen in the
pyrrolidine ring. Different conformers of the cyclohex-
ene oxide and pyrrolidine ring were also investigated. In
order to model how the solvent, THF, influences the
structure of the activated complexes, the most stable
activated complexes were optimized at the PM3, and
B3LYP/6-31G(d) level of theory, where one or two
lithium atoms in the activated complexes were specifi-
cally solvated with one or two THF molecules. Alto-
gether, about 276 unsolvated, mono-, and di-THF
solvated activated complexes were calculated at the PM3
level of theory.
5. Amedjkouh, M.; Pettersen, D.; Nilsson Lill, S. O.;
€
Davidsson, O.; Ahlberg, P. Chem. Eur. J. 2001, 7, 4368–
4
377.
. Amedjkouh, M. Tetrahedron: Asymmetry 2004, 15, 573–
46.
. Olsson, R. I.; Ahlberg, P. Tetrahedron: Asymmetry 1999,
0, 3991–3998.
6
7
7
1
8
9
. Collum, D. B. Acc. Chem. Res. 1993, 26, 227–234.
. Pettersen, D.; Amedjkouh, M.; Nilsson Lill, S. O.; Dahl ꢀe n,
K.; Ahlberg, P. J. Chem. Soc., Perkin Trans. 2 2001, 9,
1654–1661.
10. Anders, E.; Koch, R.; Freunscht, P. J. Comput. Chem.
993, 14, 1301–1312.
1
1
1
1. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209–220.
2. Hehre, W. J.; Deppmeier, B. J.; Driessen, A. J.; Johnson,
J. A.; Klunzinger, P. E.; Lou, L.; Yu, J.; Baker, J.;
Carpenter, J. E.; Dixon, R. W.; Fielder, S. S.; Johnson, H.
C.; Kahn, S. D.; Leonard, J. M.; Pietro, W. J. Spartan v.
5
.0.1; Wavefunction: Irvine, CA, 1997.
ꢀ
1
3. Csonka, G. I.; Angy ꢀa n, J. G. J. Mol. Struct. 1997, 393, 31–
8.
3
4. Csonka, G. I. J. Comput. Chem. 1993, 14, 895–898.
1
1
€
5. Hilmersson, G.; Arvidsson, P. I.; Davidsson, O.; H ꢁa kans-
Acknowledgements
son, M. J. Am. Chem. Soc. 1998, 120, 8143–8149.
6. Abbotto, A.; Streitwieser, A.; Schleyer, P. v. R. J. Am.
Chem. Soc. 1997, 119, 11255–11268.
1
1
1
1
We thank the Swedish Research Council for financial
support and the National Supercomputer Centre in
Link o€ ping, Sweden, for computational resources.
7. Thummel, R. P.; Rickborn, B. J. Am. Chem. Soc. 1970, 92,
2
064–2067.
8. Morgan, K. M.; Gajewski, J. J. J. Org. Chem. 1996, 61,
20–821.
9. Manuscript (in preparation).
8
References and notes
20. Becke, A. D. J. Chem. Phys. 1993, 98, 1372–1377.
1. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens.
Matter 1988, 37, 785–789.
22. Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys.
1972, 56, 2257–2261.
23. Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys.
1984, 80, 3265–3269.
24. Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,
213–222.
2
1
2
3
4
. O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439–
457.
. Asami, M.; Suga, T.; Honda, K.; Inoue, S. Tetrahedron
Lett. 1997, 37, 6425–6428.
. Bertilsson, S. K.; S o€ dergren, M. J.; Andersson, P. G.
J. Org. Chem. 2002, 67, 1567–1573.
. Pettersen, D.; Amedjkouh, M.; Ahlberg, P. Tetrahedron
1
2
002, 58, 4669–4673.
25. GAUSSIAN98; Gaussian: Pittsburgh, PA.