Asymmetric addition of n-butyllithium to aldehydes: New insights into the reactivity and enantioselectivity of the chiral amino ether accelerated reaction

Article abstract of DOI:10.1016/S0040-4020(02)00378-2

Enantioselective butylation of benzaldehyde with n-butyllithium was mediated by a series of chiral lithium amide analogues to give 1-phenylpentanol in good to moderate enantioselectivities. In order to achieve high enantiomeric excess in the reaction, the lithium amide must have a substituent larger than methyl on both the carbon at the stereogenic center and the nitrogen. Computational studies, using semi-empirical (PM3) and density functional (B3LYP) methods, show that the stabilities of the transition states for the chiral lithium amide accelerated butylation of isobutyraldehyde are in agreement with experiments.

Full text of DOI:10.1016/S0040-4020(02)00378-2

TETRAHEDRON
Pergamon
Tetrahedron 58 ,2002) 4717±4725
Asymmetric addition of n-butyllithium to aldehydes:
new insights into the reactivity and enantioselectivity
of the chiral amino ether accelerated reaction
p
È
Johan Granander, Richard Sott and Goran Hilmersson
È È
Organic Chemistry, Department of Chemistry, Goteborg University, S-412 96 Goteborg, Sweden
Received 20 December 2001; accepted 5 March 2002
AbstractÐEnantioselective butylation of benzaldehyde with n-butyllithium was mediated by a series of chiral lithium amide analogues to
give 1-phenylpentanol in good to moderate enantioselectivities. In order to achieve high enantiomeric excess in the reaction, the lithium
amide must have a substituent larger than methyl on both the carbon at the stereogenic center and the nitrogen. Computational studies, using
semi-empirical ,PM3) and density functional ,B3LYP) methods, show that the stabilities of the transition states for the chiral lithium amide
accelerated butylation of isobutyraldehyde are in agreement with experiments. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
observed an equilibrium between homo complexed chiral
lithium amide dimers, tetrameric n-BuLi and a mixed
dimer consisting of one lithium amide and one n-BuLi
,Scheme 1).5
Asymmetric carbon±carbon bond forming reactions
between n-butyllithium ,n-BuLi) and aldehydes can be a
particularly versatile reaction in the construction of enantio-
pure alcohols.1 The enantioselectivity is obtained using
chiral lithium amides as chiral auxiliaries and catalysts,
non-covalently bonded to the reagent n-BuLi. Our interest
in this ®eld began in 1993 when we initiated NMR spectro-
scopic studies of a chiral lithium amide reported by
Hogeveen and Eleveld to induce asymmetry in the addition
of n-BuLi to benzaldehyde.2,3 So far, the enantioselectivities
obtained with organolithium compounds in the alkylation
reaction of aldehydes have not been as high as those with
dialkyl zinc reagents.4 However, the readily available alkyl-
lithium reagents and their high reactivity are properties that
motivate more effort to ®nd conditions in which organo-
lithium compounds also can become useful nucleophilic
reagents in asymmetric synthesis.
Most of the NMR spectroscopic studies were carried out in
diethyl ether ,DEE) solution. Later, the effect of different
solvents and substituents on the equilibrium and enantio-
selectivity of addition to an aldehyde were investigated.6
At that time, our results indicated the importance of a
high complexation constant in order to observe high
enantioselectivity. Since then, we have remained in this
®eld with the aim of better understanding the factors
governing the enantioselectivity. This work includes the
search for new mixed complexes between n-BuLi and chiral
inducers. We hope that details regarding this issue could
be helpful in the design of new and more ef®cient chiral
inducers for this important class of reaction. Herein, we
report our continued studies of chiral lithium amides and
their use in the asymmetric addition reaction to prochiral
aldehydes. Based on quantum chemical calculations we also
By low temperature NMR spectroscopic studies we have
Scheme 1.
Keywords: lithium; amides; alkylation; asymmetric.
Corresponding author. Tel./fax: 146-31-7722904; e-mail: hilmers@organic.gu.se
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00378-2

4718
J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
coordinating solvents, e.g. DEE, a 50:50 mixture of
dimethoxy methane ,DMM) and DEE and a 50:50 mixture
of DEE and tetrahydrofuran ,THF). In addition, a few of the
reactions were also performed in a 50:50 mixture of pentane
and toluene ,pent/tol), a non-coordinating solvent mixture.
Scheme 2.
All chiral lithium amides catalyzed the formation of the
alcohol with the opposite con®guration compared to that
of the amide. This indicates that the reaction is robust in
nature even though it requires the formation of a hetero-
complex.
propose transition state structures that explain the observed
enantioselectivity.
Previous studies only involved phenylsubstituted lithium
amides while this work also includes aliphatic R groups.
The enantioselectivity obtained with the various lithium
amides indicates that the phenyl group is not crucial to
obtain high enantioselectivity. Replacing the phenyl ring
with an isopropyl group results in similar enantioselectivity
in the asymmetric alkylation reaction. This shows that it
is the steric requirements of the R group and not the
stereo-electronic effects of having the phenyl substituent
that are crucial for high enantioselectivity.
2. Results and discussion
2.1. Enantioselectivity and steric requirements
Often in organolithium chemistry small changes in ligand
structure or reaction conditions result in large effects on
organolithium structure and/or enantioselectivity. However,
the amino ether catalyzed system for addition of n-BuLi
to aldehydes is a particularly robust and reliable system
allowing a large number of modi®cations to be studied.
From the results of Table 1 it is clear that a methyl group, as
in the alanine derivative 1a, is not large enough to induce
asymmetry in the alkylation reaction. We believe that
the asymmetry in the reaction comes from the steric require-
ments of the alkyl group on the nitrogen. The chirality of the
nitrogen is transferred from the carbon to the lithium amide
nitrogen. Based on this, it is evident that a methyl group on
the lithium amide nitrogen yields very low enantioselec-
tivity. However, with a secondary carbon on the amide
nitrogen, a much higher enantioselectivity was achieved.
Among these larger substituents there are small differences,
i.e. isopropyl, 3-pentyl or cyclohexyl on the nitrogen result
in approximately the same enantioselectivity. In DEE, the
highest enantioselectivity was found with the isopropyl
The amino ethers were prepared in high yield from readily
available amino acids. The amino acids were ®rst reduced
using lithium aluminum hydride. Alkylation of the amine
in two steps via the imine yielded the secondary amino
alcohols, which were then converted into the respective
amino ethers.
We have focused our modi®cations to three positions of the
amino ether: the alkyl group ,R0) on the nitrogen, the alkyl
group on the oxygen ,R00) and the bulky group attached to
the stereogenic center ,R) ,Scheme 2). The results of the
stereoselective alkylation of benzaldehyde employing
lithium amides 1±4 are given in Table 1. The reactions
have mainly been performed in three different ethereal or
Table 1. Asymmetric alkylation of benzaldehyde ,0.10 equiv.) with n-BuLi ,0.45 equiv.) in the presence of chiral lithium amides 1a, 2a±j, 3a±c and 4a±e
,1.0 equiv.), resulting in alcohols with con®guration opposite to that of the lithium amide. The reactions were performed in four different solvents or solvent
mixtures at 21168C. All reactions proceeded in quantitative yield according to the chiral stationary phase GC analysis
Li-amide
R
R0
R00
ee ,%)
DEE/THF
DEE
DEE/DMM
Pentane/toluene
,S)-1a
,R)-2a
,S)-2b
,S)-2c
,S)-2d
,S)-2e
,S)-2f
,S)-2g
,S)-2h
,R)-2i
,R)-2j
,S)-3a
,S)-3b
,S)-3c
,S)-4a
,S)-4b
,S)-4c
,S)-4d
,S)-4e
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
i-Pr
Me
i-Pr
i-Pr
Me
Me
Me
Et
i-Pr
Me
Et
Me
Et
Me
Et
Me
Et
i-Pr
Me
Et
i-Pr
Me
Et
36
2a
±
±
±
±
±
±
±
±
±
±
±
17
±
±
8
38
±
±
8
±
±
±
20
82a
60
50
48
29
75
66
6
91a
76
73
63
63
87
86
27
32
68
74
74
78
76
77
29
32
85
79
77
72
70
86
89
47
45
67
69
72
78
74
71
42
48
i-Pr
3-Pentyl
3-Pentyl
Cyclohexyl
Cyclohexyl
2-Methoxybenzyl
2-Methoxybenzyl
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
2
Benzyl
Benzyl
Benzyl
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
60
41
52
61
44
48
15
17
i-Pr
2-Methoxybenzyl
2-Methoxybenzyl
a
Ref. 6.

J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
4719
result shows that the lithium amides may also be used for
asymmetric alkylation of prochiral ketones.
2.2. Enantioselectivity versus mixed complex formation
Our preliminary results indicated that the high degree of
complexation between the chiral lithium amide and the
nucleophile n-BuLi is prerequisite for success in the asym-
metric reaction. This was supported by the low enantio-
selectivities obtained with diamines, which generally gave
lower amounts of mixed complexes. However, it is impor-
tant to take into account the concentrations used in these
asymmetric reactions. Even if the apparent equilibrium
constants differ by ®ve orders of magnitude, the actual
concentration of reactive n-BuLi/Li-amide differ by less
than a factor of 2 ,[n-BuLi/Li-amide]<0.03±0.05 M).
Although the concentration of free tetrameric n-BuLi varies
at the same time from 0.005 M to an in®nitely small number
,,1025 M).
Scheme 3.
Thus there is only a weak correlation between the equi-
librium constant and the observed enantioselectivity, due
to the fact that the amount of uncomplexed n-BuLi at the
studied concentrations is low compared to the amount
complexed. Below, we have based the calculations on the
actual equilibrium constants and the total concentrations
calculated from the theoretical concentrations of free
tetrameric n-BuLi and lithium amide/n-BuLi complexes.
group. But in the DMM/DEE and THF/DEE mixtures
we found that cyclohexyl gave similar values of enantio-
selectivity compared to isopropyl.
There is a very small dependence on the enantioselectivity
versus the size of the alkyl group of the ether. Methyl-,
ethyl-, and isopropyl ethers yield about the same chiral
induction. Although, generally the methyl is the better
followed by ethyl and isopropyl.
‰Li-amideŠ ˆ 0:116 M; ‰n-BuLiŠ
tot
tot
We also investigated some tridentate lithium amides as
chiral inducers. Similar chiral tridentate amines have been
reported to achieve high enantioselectivity in the asym-
metric addition of methyllithium to imines.7 Our tridentate
amines were formed by condensing 2-methoxybenz-
aldehyde with chiral amino alcohols followed by reduction
and alkylation of the alcohol. However, the enantio-
selectivities of the butylation of benzaldehyde were dis-
appointing with ees up to 48% at most. Only low
enantioselectivities were observed for all lithium amides
employed in the non-coordinating solvents. The solvent
dependence of the enantioselectivity was larger for the
tridentate lithium amides than for the bidentate, despite
their additional coordinating group. Interestingly, the enan-
tioselectivities are similar for these amides in DEE and in
the non-coordinating solvent mixture. This indicates that the
transition state structures could be similar. Possibly there
are mixed dimers in both DEE and the non-coordinating
solvent mixture and DEE is not capable of solvating the
mixed dimer while THF is. Altogether, the enantioselec-
tivity appears to be signi®cantly in¯uenced by the solvent,
indicating that coordinating solvent molecule,s) are
involved in the rate determining activated complex.
ˆ 0:052 Mꢀ0:45 equiv:†
Kˆ0.1 M)
[Li-amide/n-BuLi]ˆ0.032 M; [,n-BuLi)4]ˆ 0.0051 M
Kˆ4 M)
[Li-amide/n-BuLi]ˆ0.048 M; [n-BuLi)4]ˆ 0.0011 M
Kˆ10,000 M)
[Li-amide/n-BuLi]ˆ0.052 M; [,n-BuLi)4]ˆ ,1025
M
It is also found that most of the n-BuLi is present in the
mixed complex even when the equilibrium constant is as
small as 4. The [,n-BuLi)4] concentration is less than 25% of
the concentration [Li-amide/n-BuLi]. Since the asymmetric
alkylation reactions are performed with only 0.25 equiv. or
less of the aldehyde and the mixed complex is much more
reactive than tetrameric n-BuLi,9 we conclude that the
amount of aldehyde that reacts via tetrameric n-BuLi is
consequently only a fraction even when the equilibrium
constant is unfavorable.
2.3. NMR spectroscopy
We have previously reported on the solution structures of
the lithium amides 2b and 4a and have now studied 3a and
the tridentate 1j by NMR spectroscopy.6 There is only a
small solvent dependence between different coordinating
solvents. However, there is a pronounced change upon
going from an ether solvent to a non-coordinating solvent.
All investigated lithium amides in this series form mixed
dimers with n-BuLi in coordinating solvents. The equi-
librium constants vary signi®cantly, but the fundamental
equilibrium is the same. However, in non-coordinating
To test the versatility of the asymmetric alkylation reactions
we also added methyllithium to benzaldehyde with the
bidentate chiral lithium amide 4a as chiral inducer.
However, the results were not promising, an enantioselec-
tivity of 45% was observed in THF/DEE. Surprisingly, the
tridentate amide 4e that we believed would be more success-
ful generated only racemic mixtures of the methyl adduct.
The butylation of tri¯uoroacetophenone mediated by 4e was
found to proceed with 58% ee in THF/DEE. This promising

4720
J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
Figure 1. Schematic drawings of the calculated transition state structures ,R)-TS and ,S)-TS for the alkylation with the mixed dimer lithium amide 4a/n-BuLi
yielding ,R)-alcohol and ,S)-alcohol. The DFT calculations were performed at the B3LYP/6-31G1,d)//PM3 level of theory. Distances are given in Angstrom
21
Ê
,A) and the relative energies are given in kcal mol
.
solvents mixed trimers, containing two lithium amides and
one n-BuLi, of the type found by Williard dominate.8 Two
lithium amides, 3a and 4a form this sort of complex as
found by NMR spectroscopy. These trimers are C2-sym-
metric and should have potential as chiral nucleophiles.
reaction with methanol are about the same. The presence
of the lithium amides 2b and 3a did not make any consider-
able difference. Thus addition of 1 mL methanol to quench
the reaction is suf®cient to remove all available n-BuLi
instantaneously.
2.4. Reactivity studies
2.5. Computational studies
How important are the steric requirements of the R-group of
the aldehyde for the reaction rate? The alkylation reactions
are irreversible and if several aldehydes are added simul-
taneously there are as many concurrent independent modes
of reaction ,Scheme 3). However, the product compositions
in such parallel reactions are directly related to their indi-
vidual rate constants. In separate experiments, a mixture of
two different aldehydes, both in excess ,each in 5 equiv.),
were added to n-BuLi ,1 equiv.) and to the mixture of
n-BuLi/lithium amide ,1 equiv.), respectively. With no
lithium amide present, benzaldehyde was found to react
13 times faster than cyclohexanecarboxaldehyde with
n-BuLi in DEE at 21168C. However, in the presence of
the lithium amide 2b, the reaction rate was only 1.4 times
higher. The reaction of isobutyraldehyde was 3.2 times
faster than cyclohexanecarboxaldehyde without catalyst
present but 1.6 times slower in the presence of 2b. Appar-
ently, 2b catalyzes the alkylation of cyclohexanecarbox-
aldehyde more ef®ciently than benzaldehyde and iso-
butyraldehyde. The alkylation reactions of isobutyraldehyde
and cyclohexanecarboxaldehyde mediated by 2b resulted in
ees of .8.5% higher than that of benzaldehyde.9 Therefore,
it is surprising to ®nd a large difference in accelerating not
only between benzaldehyde and cyclohexancarboxaldehyde
but also between isobutyraldehyde and cyclohexanecarbox-
aldehyde.
The asymmetric alkylation reaction must proceed through a
transition state consisting of a complex between a chiral
lithium amide, n-BuLi and the aldehyde in order to observe
enantioselectivity. We have studied this reaction using the
semi-empirical PM3 method with Anders parameters for
lithium to obtain geometries of high quality and then single
point DFT calculations of the energies were performed.10
This method has previously been employed with good
results by several groups in the ®eld.11
The lithium amide 4a was chosen as chiral lithium amide in
the calculations since this lithium amide is the smallest
amongst the investigated amides that still results in good
selectivity. We used dimethyl ether as the solvent. There
are several possible conformers of the ground state structure
according to the PM3 calculations, considering the coordi-
nation of the prochiral aldehyde. The interconversion
among the different conformers is assumed to follow the
Curtin±Hammett principle. Thus, the dDG between the
favored transition states leading to the ,R)- and the ,S)-alco-
hols should be responsible for the enantioselectivity
observed experimentally.
The favored transition states for the transfer of the butyl
group to the carbonyl are shown in Fig. 1. We observed a
large gain in enthalpy of solvation by adding one ether to the
lithium coordinated by isobutyraldehyde. However, there
was no gain of solvation upon adding a second ether to
the tri-coordinated lithiums. Apparently, the steric
hindrance at the tri-coordinated lithiums is too large to
accommodate a coordinating ether.
What is the reactivity of n-BuLi vs aldehyde and methanol,
respectively? Methanol is usually used to quench these
types of reactions and has previously been used in an
attempt to measure the reaction rate of the alkylation of
aldehydes.9 Alkylation experiments in the presence of 1,
10 and 50 equiv. of methanol show that the rate of the
alkylation reaction of benzaldehyde and the quenching
At the B3LYP,6-311G,d))//PM3 level of theory it appears
that transition state ,R)-TS is 3.4 kcal mol21 less stable than

J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
4721
Table 2. Enantiomeric excesses obtained from the addition of n-BuLi to
benzaldehyde with 3a as chiral auxiliary at various temperatures
calculations are performed in vacuum, the addition of
solvent continuum could lead the calculations closer to the
experimentally observed values.
T ,8C)
ee ,%)
Pentane/toluene
DEE/THF
2.6. Temperature dependence of the asymmetric
alkylation reaction
2116
278
246
221
0
67.3
47.6
31.6
23.9
18.9
10.3
38.2
25.9
18.1
17.9
17.9
13.4
The asymmetric alkylation reaction was also studied as a
function of temperature to obtain the absolute difference in
free energies, dDG , of the two diastereomeric transition
³
20
states leading to the enantiomers of the product and its
temperature dependence. Is the selectivity between the R
and S transition states due to entropy or enthalpy of acti-
³
³
,S)-TS, qualitatively in agreement with the experimental
results which give the ,S)-alcohol. Interestingly, the
Ê
methoxy coordinated lithium is located 4 A away from the
vation? The dDS and dDH terms for the asymmetric alkyl-
ation, employing 3a as chiral auxiliary, were determined
from the temperature dependence of dDG in both DEE/
³
a-carbon of n-BuLi in ,R)-TS. This transition state is an
open dimer transition state. Such structures have been
suggested previously to be important in the reaction
between an aldehyde and methyllithium.12 This appears to
be due to a larger steric hindrance in ,R)-TS than in ,S)-TS.
The structure of transition state ,S)-TS resembles a ladder
structure of a lithium amide ,i.e. a trimer). At the B3LYP-
,6-311G,d))//PM3, a second transition state with a shorter
methoxy-lithium distance leading to the ,R)-alcohol was
also found, but at slightly higher energy ,14.0 kcal mol21).
The central core of the respective transition states are planar
or nearly planar, i.e. the two lithiums, the amide nitrogen,
the a-carbon of n-BuLi and the carbonyl group form a
plane.
THF and pentane/toluene mixtures ,Table 2).
The alkylation reactions are irreversible, hence the rates of
formation of R and S alcohols are described by kR and kS,
with the ratio kR/kS corresponding to the molar free energy
³
difference, dDG , of the two reactions ,Fig. 2).
The enthalpic terms were determined to be 23.9 and
21.4 kJ mol21 in DEE/THF and pentane/toluene, respec-
tively. The entropy terms were 11.6 and 2.7 J K21 mol21
.
As expected, the selectivity is largely governed by entropy
in the DEE/THF mixture, since the transition states are most
likely solvated by THF. However, in a pentane/toluene
mixture the transition states are most likely unsolvated
and there is consequently less entropic differences between
the two diastereomeric transition states.
It is dif®cult to rationalize how the enantioselectivity could
be induced in these transition states. There is only one
stereogenic center in the chiral lithium amide, but in the
complex, the nitrogen and the tetracoordinated lithium
also become additional stereogenic centers. The chirality
of the carbon is thus being transferred from carbon to both
the nitrogen and the tetracoordinated lithium. If either the
alkyl group on the carbon or the nitrogen is too small, this
transfer of chirality will not be as effective resulting in a
lowering in enantioselectivity. Furthermore, the solvent
ether is also important for the enantioselectivity as can be
expected for the transition states shown in Fig. 1.
3. Conclusion
No major electronic effects are operating since phenyl
groups on either the aldehyde or lithium amide have no
effect on the enantioselectivity compared to bulky aliphatic
substituents. Isopropyl groups on the lithium amide appear
to yield the highest enantioselectivity. Chiral lithium amides
can be useful reagents for asymmetric synthesis but we still
know too little about this class of compounds for truly
rational design of new and better chiral lithium amides.
The surprisingly large effect that a seemingly small change
on the lithium amide or solvent does not have to be a
disadvantage, it can possibly also turn out to be a great
It must however be added that the error in PM3 calculations
might exceed the energy difference observed experi-
mentally corresponding to a selectivity of 98%. Since the
Figure 2. Eyring plot of the temperature dependence of the free energy difference between the two diastereomeric transition states, in DEE/THF ,V) and
pentane/toluene ,B) mixtures, respectively, for the addition of n-BuLi to benzaldehyde mediated by 3a.

4722
J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
advantage. Among several reaction pathways of similar free
energy, there is a possibility to ®ne tune reactions to proceed
in a certain wanted direction. The solvent molecules have a
large effect on the enantioselectivity of the alkylation reac-
tions. The bidentate lithium amides only show a small
difference in selectivity using different ethers, however in
the case of the tridentate lithium amides we see a much
stronger variation among DEE and THF, which indicates
that the transition states are speci®cally solvated by THF
but not with DEE.
4.4. Reduction of amino acids, general procedure
The amino acid ,1.0 equiv.) was added slowly, in small
portions, to an ice cooled solution of lithium aluminum
hydride ,2.0 equiv.) in dry THF ,40 mL g21 LiAlH4). The
mixture was allowed to react at 08C for 1 h followed by
re¯ux overnight. The solution was cooled to 08C and the
excess of LiAlH4 quenched with aqueous sodium hydroxide
,2.0 M). The precipitate was ®ltered off and extracted with
boiling THF for an hour. The combined ethereal extract was
concentrated under reduced pressure and the remaining
mixture extracted with dichloromethane. The combined
organic extract was washed with brine, dried over sodium
sulfate and the solvent evaporated under reduced pressure to
give the known amino alcohols.
4. Experimental
4.1. General
NMR spectra were recorded on a Varian 400 MHz spectro-
meter using CDCl3 as solvent. Optical rotations were
measured using a Perkin±Elmer 341 LC polarimeter. IR
spectra were recorded on a Perkin±Elmer 1600 Series
FTIR spectrometer. HRMS ,FAB) spectra were recorded
on a VG ZabSpec using a beam of Cs atoms as ionization
source and glycerol to dissolve the sample. GC analysis
were carried out using a Varian Star 3400 CX gas chro-
matograph equipped with a chiral stationary phase column
,CP-Chirasil-DEX CB, 25 m, 0.32 mm) from Chrompack.9
Analyses were done using He ,1.5 mL min21) as carrier gas
,injector 2258C, detector 2508C). Dried solvents were
distilled from sodium/benzophenone.
4.4.1. /S)-Phenylalaninol. White solid ,100%); spectral
data consistent with literature.16
4.4.2. /S)-Phenylglycinol. White solid ,95%); spectral data
consistent with literature.17±19
4.4.3. /S)-Valinol. Colorless oil ,85%); spectral data con-
sistent with literature.16,18
4.5. N-Alkylation of the amino alcohol, general
procedure
The amino alcohol ,1.0 equiv.) and the carbonyl compound
,acetone; 2.0 equiv., 3-pentanone and cyclohexanone;
1.5 equiv. or 2-methoxybenzaldehyde 1.1 equiv.) were
dissolved in dry benzene ,30 mL g21 amino alcohol) and
re¯uxed overnight with a Dean±Stark trap to collect
water. The mixture was allowed to cool and the solvent
evaporated under reduced pressure. The residue was
dissolved in dry ethanol ,30 mL g21 of amino alcohol)
and sodium borohydride ,1.5 equiv.) added in small
portions. The mixture was allowed to react at room tempera-
ture until no more gas evolved, usually after only a few
hours. Water was added and most of the ethanol evaporated.
The residue was extracted with DEE and the combined
organic extract washed with brine, dried over sodium sulfate
and the solvent evaporated under reduced pressure.
4.2. Alkylation reactions
Inside a glove box containing a nitrogen atmosphere, the
chiral amine ,0.22 mmol, 1.00 equiv.) was dissolved in the
dry solvent/solvent mixture ,2.0 mL) in a dry reaction
vessel, equipped with a septum and a magnetic stirrer bar.
The vessel was sealed and taken out of the glove box and put
under an inert atmosphere ,argon or nitrogen). n-BuLi
,129 mL, 2.5 M in hexanes, 0.32 mmol, 1.45 equiv.) was
added and the mixture kept at room temperature for
15 min. The reaction mixture was cooled to 21168C in a
liquid nitrogen/DEE cooling bath and its temperature
allowed to equilibrate for 15 min before a solution of
benzaldehyde ,18.5 mL, 1.23 M in DEE, 0.022 mmol,
0.10 equiv.) was added dropwise. After 15 min, the reaction
was quenched with methanol ,1.00 mL) and allowed to
reach room temperature before it was acidi®ed using
aqueous hydrochloric acid ,0.60 mL, 5%) and diluted with
DEE ,3.00 mL). The crude mixture containing the 1-phenyl
pentanol was analyzed on the chiral stationary phase GC.
All reactions proceeded in quantitative yields according to
the GC analysis.
4.5.1. /S)-N-Isopropylalaninol. Pale yellow oil ,60%);
spectral data consistent with literature.20
4.5.2. /S)-N-Isopropylphenylglycinol. White crystals
,90%); spectral data consistent with literature.20
4.5.3. /S)-N-/3-Pentyl)phenylglycinol. Slightly yellow
crystals ,84%); H NMR ,400 MHz, CDCl3) d 0.81 ,t,
1
4.3. Computational methods
Jˆ7.4 Hz, 3H, ,CH3CH2)2CHN), 0.87 ,t, Jˆ7.6 Hz, 3H,
,CH3CH2)2CHN), 1.28±1.39 ,m, 1H, ,CH3CH2)2CHN),
1.39±1.49 ,m, 3H, ,CH3CH2)2CHN), 2.38 ,quint., Jˆ
5.8 Hz, 1H, ,Et)2CHN), 3.48 ,dd, Jˆ8.8, 10.4 Hz, 1H,
CH2OH), 3.68 ,dd, Jˆ4.6, 10.4 Hz, 1H, CH2OH), 3.86
,dd, Jˆ4.6, 8.8 Hz, 1H, PhCHCH2), 7.27±7.31 ,m, 3H,
Geometries were optimized at PM3 level of theory. In
Spartan, the option HHon,13 was used to eliminate the too
positive HH attraction of the PM3 method. All structures
were characterized as either minimum or transition states by
frequency calculations. All energies were calculated at
the B3LYP/6-311G,d)//PM3. The calculations were per-
formed either using the Spartan program package14 or the
Gaussian98W.15
20
Ph), 7.33±7.38 ,m, 2H, Ph); [a]D ˆ181.8 ,c 2.9, ethanol);
n
max ,KBr) 3155 ,br), 1146, 1066, 1041, 1029 cm21; HRMS
,FAB): MH1, found 208.1663. C13H22NO requires
208.1701.

J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
4723
4.5.4. /S)-N-Cyclohexylphenylglycinol. Colorless needle-
shaped crystals, recrystallized from ethyl acetate/hexane
mixture was allowed to react at room temperature for 2 h
before the alkylating reagent ,methyl iodide 1.0 equiv.,
ethyl iodide 1.5 equiv., p-toluenesulfonic acid isopropyl
ester 2.0 equiv.) was added. The mixture was then left to
react at room temperature overnight ,when p-toluenesul-
fonic acid isopropyl ester was used the mixture was re¯uxed
overnight). Distilled water was added and the ethereal
solvent removed under reduced pressure. The residue was
extracted with dichloromethane and the combined extract
washed with brine, dried over sodium sulfate and the solvent
removed under reduced pressure. KuÈgelrohr distillation
under reduced pressure afforded the respective amines as
colorless oils.
1
25:75 ,70%); H NMR ,400 MHz, CDCl3) d 1.04±1.22
,m, 5H, ,CH2)5CHN), 1.57 ,m, 1H, ,CH2)5CHN), 1.66±
1.72 ,m, 3H, ,CH2)5CHN), 1.97 ,m, 1H, ,CH2)5CHN),
2.42 ,m, 1H, ,CH2)5CHN), 3.47 ,dd, Jˆ9.4, 10.4 Hz, 1H,
CH2OH), 3.67 ,dd, Jˆ4.4, 10.4 Hz, 1H, CH2OH), 3.94 ,dd,
Jˆ4.4, 9.4 Hz, 1H, PhCHCH2), 7.27±7.32 ,m, 3H, Ph),
20
7.34±7.39 ,m, 2H, Ph); [a]D ˆ175.2 ,c 2.5, ethanol);
nmax ,KBr) 3270, 3132 ,br), 1500, 1451, 1040 cm21
;
HRMS ,FAB): MH1, found 220.1659. C14H22NO requires
220.1701.
4.5.5. /R)-N-/2-Methoxybenzyl)phenylglycinol. Colorless
rhombic crystals, recrystallized from ethyl acetate/hexane
4.7.1. /S)-N-Isopropyl-O-methylalaninol /1a). Colorless
oil ,40%); spectral data consistent with literature.20
1
20:80 ,70%); H NMR ,400 MHz, CDCl3) d 3.58 ,m, 2H,
ArCH2N), 3.73 ,m, 1H, PhCHCH2), 3.81 ,m, 2H,
PhCHCH2), 3.82 ,s, 3H, CH3O), 6.84±6.94 ,m, 2H, Ar),
7.19 ,m, 1H, Ar), 7.24 ,m, 1H, Ar), 7.27±7.39 ,m, 5H,
4.7.2. /R)-N-Methyl-O-methylphenylglycinol /2a). This
compound was prepared according to literature methods.5
20
Ph); [a]D ˆ291.6 ,c 4.4, ethanol); nmax ,KBr) 3315,
3164 ,br) 1239, 1124, 1045 cm21; HRMS ,FAB): MH1,
found 258.1456. C16H20NO2 requires 258.1494.
4.7.3. /S)-N-Isopropyl-O-methylphenylglycinol /2b). Color-
less oil ,90%); spectral data consistent with literature.20,22,23
4.5.6. /S)-N-Isopropylphenylalaninol. White solid ,95%);
4.7.4. /S)-N-Isopropyl-O-ethylphenylglycinol /2c). Color-
less oil ,80%); H NMR ,400 MHz, CDCl3) d 0.99 ,d,
spectral data consistent with literature.20
1
Jˆ6.4 Hz, 3H, ,CH3)2CHN), 1.05 ,d, Jˆ6.4 Hz, 3H,
,CH3)2CHN), 1.20 ,t, Jˆ7.0 Hz, 3H, CH3CH2O), 2.65
,sept., Jˆ6.3 Hz, 1H, ,Me)2CHN), 3.40 ,t, Jˆ9.2 Hz, 1H,
PhCHCH2), 3.46±3.55 ,m, 3H, PhCHCH2 and CH3CH2O),
4.02 ,dd, Jˆ4.0, 8.8 Hz, 1H, PhCHCH2), 7.25±7.28 ,m, 1H,
Ph), 7.31±7.35 ,m, 2H, Ph), 7.36±7.39 ,m, 2H, Ph);
4.5.7. /S)-N-Isopropylvalinol. Colorless oil ,80%); spectral
data consistent with literature.20
4.5.8. /S)-N-/2-Methoxybenzyl)valinol. White crystals
1
,50%); H NMR ,400 MHz, CDCl3) d 1.0 ,d, Jˆ6.8 Hz,
20
3H, ,CH3)2CHC), 1.02 ,d, Jˆ6.8 Hz, 3H, ,CH3)2CHC),
2.14 ,m, 1H, ,CH3)2CHC), 2.70 ,s ,broad), 1H, i-PrCHCH2),
3.82 ,s ,broad), 2H, CHCH2OH), 3.94 ,s, 3H, CH3O), 4.22
,d, Jˆ13.2 Hz, 1H, ArCH2N), 4.30 ,d, Jˆ13.2 Hz, 1H,
ArCH2N), 6.91±7.00 ,m, 2H, Ar), 7.35±7.40 ,m, 1H, Ar),
[a]D ˆ168.4 ,c 3.6, ethanol); nmax ,liquid ®lm) 3327,
1107 cm21
C13H22NO requires 208.1701.
;
HRMS ,FAB): MH1, found 208.1708.
4.7.5. /S)-N-Isopropyl-O-isopropylphenylglycinol /2d).
Colorless oil ,40%); H NMR ,400 MHz, CDCl3) d 0.98
20
1
7.43±7.47 ,m, 1H, Ar); [a]D ˆ17.0 ,c 1.7, ethanol); nmax
,KBr) 3348 ,br) 1245, 1026 cm21; HRMS ,FAB): MH1,
found 224.1617. C13H22NO2 requires 224.1651.
,d, Jˆ6.4 Hz, 3H, ,CH3)2CHN), 1.05 ,d, Jˆ6.4 Hz, 3H,
,CH3)2CHN), 1.15 ,t, Jˆ6.0 Hz, 6H, ,CH3)2CHO), 2.65
,sept., Jˆ6.4 Hz, 1H, ,CH3)2CHN), 3.35 ,t, Jˆ9.2 Hz, 1H,
PhCHCH2), 3.52 ,dd, Jˆ4.0, 9.2 Hz, 1H, PhCHCH2), 3.58
,sept., Jˆ6.0 Hz, 1H, ,CH3)2CHO), 3.97 ,dd, Jˆ4.0, 9.2 Hz,
1H, PhCHCH2), 7.25±7.28 ,m, 1H, Ph), 7.30±7.35 ,m, 2H,
4.6. p-Toluenesulfonic acid isopropyl ester
A solution of 2-propanol ,6.00 g, 7.64 mL, 100 mmol,
1.0 equiv.) in dry pyridine ,200 mL) was cooled to 08C
and p-toluenesulfonic acid chloride ,28.60 g, 150 mmol,
1.5 equiv.) was added in small portions over 15 min. The
mixture was allowed to react overnight while warming to
room temperature. The mixture was then poured onto
crushed ice ,200 g). The resulting mixture was extracted
with 7£50 mL DEE. The combined organic extract was
washed with 4£50 mL aqueous hydrochloric acid ,6.0 M),
4£50 mL aqueous sodium bicarbonate ,saturated),
4£50 mL brine, dried over sodium sulfate and the solvent
removed under reduced pressure yielding the product as a
clear, slightly yellowish oil ,17.94 g, 85%). Spectral data
consistent with literature.21
20
Ph), 7.37±7.40 ,m, 2H, Ph); [a]D ˆ163.7 ,c 3.0, ethanol);
nmax ,liquid ®lm) 3327, 1127, 1074 cm21; HRMS ,FAB):
MH1, found 222.1851. C14H24NO requires 222.1858.
4.7.6. /S)-N-/3-Pentyl)-O-methylphenylglycinol /2e).
Colorless oil ,40%); H NMR ,400 MHz, CDCl3) d 0.83
1
,t, Jˆ7.4 Hz, 6H, ,CH3CH2)2CHN), 1.24±1.39 ,m, 2H,
,CH3CH2)2CHN), 1.41±1.48 ,m, 2H, ,CH3CH2)2CHN),
2.25 ,m, 1H, ,Et)2CHN), 3.36 ,s, 3H, OCH3), 3.41 ,m,
2H, PhCHCH2), 4.01 ,dd, Jˆ4.8, 8.0 Hz, 1H, PhCHCH2),
7.23±7.28 ,m, 2H, Ph), 7.30±7.35 ,m, 2H, Ph), 7.37±7.41
20
,m, 1H, Ph); [a]D ˆ171.1 ,c 2.8, ethanol); nmax ,liquid
®lm) 3338, 1120 cm21; HRMS ,FAB): MH1, found
222.1829. C14H24NO requires 222.1858.
4.7. O-Alkylation, general procedure
4.7.7. /S)-N-/3-Pentyl)-O-ethylphenylglycinol /2f). Color-
less oil ,60%); H NMR ,400 MHz, CDCl3) d 0.83 ,m,
6H, ,CH3CH2)2CHN), 1.20 ,t, Jˆ7.2 Hz, 3H, CH3CH2O),
1.22±1.36 ,m, 2H, ,CH3CH2)2CHN), 1.45 ,m, 2H,
,CH3CH2)2CHN), 2.26 ,m, 1H, ,Et)2CHN), 3.40 ,t, Jˆ
1
The amino alcohol ,1.0 equiv.), dissolved in dry THF
,15 mL g21 of amino alcohol), was added to a suspension
of sodium hydride ,1.5 equiv., 60% dispersion in mineral
oil) in dry THF ,100 mL g21 of sodium hydride). The

4724
J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
9.0 Hz, 1H, PhCHCH2), 3.45±3.58 ,m, 3H, PhCHCH2 and
CH3CH2O), 3.99 ,dd, Jˆ3.8, 9.0 Hz, 1H, PhCHCH2), 7.23±
7.27 ,m, 1H, Ph), 7.30±7.34 ,m, 2H, Ph), 7.38±7.41 ,m, 2H,
,CH3)2CHN), 1.26 ,t, Jˆ6.8 Hz, 3H, CH3CH2O), 2.82 ,m,
2H, ,PhCH2), 2.99 ,sept., Jˆ6.4 Hz, 1H, ,CH3)2CHN), 3.08
,m, 1H, PhCH2CHCH2), 3.34 ,m, 2H, PhCH2CHCH2), 3.52
,m, 2H, CH3CH2O), 7.22±7.32 ,m, 3H, Ph), 7.33±7.39 ,m,
20
Ph); [a]D ˆ173.5 ,c 3.0, ethanol); nmax ,liquid ®lm) 3340,
20
1109 cm21
C15H26NO requires 236.2014.
;
HRMS ,FAB): MH1, found 236.2052.
2H, Ph); [a]D ˆ113.8 ,c 3.1, ethanol); nmax ,liquid ®lm)
3322, 1113 cm21; HRMS ,FAB): MH1, found 222.1873.
C14H24NO requires 222.1858.
4.7.8. /S)-N-Cyclohexyl-O-methylphenylglycinol /2g).
Colorless oil ,80%); H NMR ,400 MHz, CDCl3) d 0.98±
1
4.7.14. /S)-N-Isopropyl-O-isopropylphenylalaninol /3c).
Colorless oil ,10%); H NMR ,400 MHz, CDCl3) d 0.99
1
1.18 ,m, 5H, ,CH2)5CHN), 1.54 ,m, 1H, ,CH2)5CHN),
1.62±1.73 ,m, 3H, ,CH2)5CHN), 2.02 ,m, 1H,
,CH2)5CHN), 2.28 ,m, 1H, ,CH2)5CHN), 3.36 ,s, 3H,
OCH3), 3.37 ,dd, Jˆ8.8, 9.2 Hz, 1H, CH2OMe), 3.43 ,dd,
Jˆ4.0, 9.2 Hz, 1H, CH2OMe), 4.09 ,dd, Jˆ4.0, 8.8 Hz, 1H,
PhCHCH2), 7.24±7.29 ,m, 1H, Ph), 7.31±7.39 ,m, 4H, Ph);
,d, Jˆ6.4 Hz, 3H, ,CH3)2CHN), 1.05 ,d, Jˆ6.4 Hz, 3H,
,CH3)2CHN), 1.14 ,d, Jˆ6.0 Hz, 3H, ,CH3)2CHO),
1.15 ,d, Jˆ6.0 Hz, 3H, ,CH3)2CHO), 2.76 ,m, 2H,
PhCH2CHCH), 2.93 ,sept., Jˆ6.4 Hz, 1H, ,CH3)2CHN),
2.99 ,m, 1H, PhCH2CHCH2), 3.27 ,m, 2H, PhCH2CHCH2),
3.52 ,sept., Jˆ6.0 Hz, 1H, ,CH3)2CHO), 7.17±7.23 ,m, 3H,
20
[a]D ˆ175.4 ,c 2.3, ethanol); nmax ,liquid ®lm) 3328,
1110 cm21
C15H24NO requires 234.1858.
;
HRMS ,FAB): MH1, found 234.1886.
Ph), 7.27±7.32 ,m, 2H, Ph); [a]D ˆ114.2 ,c 2.6, ethanol);
20
nmax ,liquid ®lm) 3323, 1173, 1128, 1080 cm21; HRMS
,FAB): MH1, found 236.2011. C15H26NO requires
236.2014.
4.7.9. /S)-N-Cyclohexyl-O-ethylphenylglycinol /2h).
Colorless oil ,90%); 1H NMR ,400 MHz, CDCl3) d
1.00±1.18 ,m, 5H, ,CH2)5CHN), 1.20 ,t, Jˆ7.0 Hz, 3H,
CH3CH2O), 1.54 ,m, 1H, ,CH2)5CHN), 1.63±1.74 ,m, 3H,
,CH2)5CHN), 2.02 ,m, 1H, ,CH2)5CHN), 2.29 ,m, 1H,
,CH2)5CHN), 3.77 ,t, Jˆ9.2 Hz, 1H, PhCHCH2), 3.46±
3.56 ,m, 3H, PhCHCH2 and CH3CH2O), 4.09 ,dd, Jˆ4.0,
9.2 Hz, 1H, PhCHCH2), 7.25±7.28 ,m, 1H, Ph), 7.30±7.35
4.7.15. /S)-N-Isopropyl-O-methylvalinol /4a). Colorless
oil ,60%); spectral data consistent with literature.20,22,23
4.7.16. /S)-N-Isopropyl-O-ethylvalinol /4b). Colorless oil
1
,60%); H NMR ,400 MHz, CDCl3) d 0.92 ,d, Jˆ7.2 Hz,
6H, ,CH3)2CHC), 1.05 ,d, Jˆ6.2 Hz, 3H, ,CH3)2CHN), 1.05
,d, Jˆ6.2 Hz, 3H, ,CH3)2CHN), 1.19 ,t, Jˆ6.8 Hz, 3H,
CH3CH2O), 1.85 ,m, 1H, ,CH3)2CHC), 2.55 ,q, Jˆ5.6 Hz,
1H, i-PrCHCH2), 2.86 ,sept., Jˆ6.2 Hz, 1H, ,CH3)2CHN),
3.22 ,dd, Jˆ5.6, 9.4 Hz, 1H, i-PrCHCH2), 3.41 ,dd, Jˆ5.6,
9.4 Hz, 1H, i-PrCHCH2), 3.48 ,q, Jˆ6.8 Hz, 2H,
20
,m, 2H, Ph), 7.36±7.40 ,m, 2H, Ph); [a]D ˆ170.1 ,c 2.3,
ethanol); nmax ,liquid ®lm) 3326, 1110 cm21; HRMS
,FAB): MH1, found 248.2016. C16H26NO requires
248.2014.
20
4.7.10. /R)-N-/2-Methoxybenzyl)-O-methylphenylglycinol
/2i). Colorless oil ,40%); H NMR ,400 MHz, CDCl3) d
CH3CH2O); [a]D ˆ23.6 ,c 2.9, ethanol); nmax ,liquid
1
®lm) 3327, 1173, 1119 cm21; HRMS ,FAB): MH1, found
3.31 ,s, 3H, CH3OCH2), 3.41±3.45 ,m, 2H, PhCHCH2),
3.55 ,d, Jˆ13.4 Hz, 1H, ArCH2N), 3.74 ,d, Jˆ13.4 Hz,
1H, ArCH2N), 3.83 ,s, 3H, CH3OAr), 3.92 ,dd, Jˆ5.4,
7.8 Hz, 1H, PhCHCH2), 6.83±6.94 ,m, 2H, Ar), 7.13±7.16
174.1889. C10H24NO requires 174.1858.
4.7.17. /S)-N-Isopropyl-O-isopropylvalinol /4c). Color-
less oil ,25%); H NMR ,400 MHz, CDCl3) d 0.90 ,d,
1
,m, 1H, Ar), 7.20±7.25 ,m, 1H, Ar), 7.25±7.31 ,m, 1H, Ph),
Jˆ6.4 Hz, 6H, ,CH3)2CHCH), 1.04 ,m, 6H, ,CH3)2CHN),
1.14 ,d, Jˆ6.0 Hz, 6H, ,CH3)2CHO), 1.83 ,m, 1H,
,CH3)2CHCH), 2.50 ,m, 1H, i-PrCHCH2), 2.84 ,sept.,
Jˆ6.4 Hz, 1H, ,CH3)2CHN), 3.29 ,m, 1H, i-PrCHCH2),
3.39 ,m, 1H, i-PrCHCH2), 3.52 ,sept., Jˆ6.0 Hz, 1H,
®lm) 3330, 1174, 1127, 1085 cm21; HRMS ,FAB): MH1,
found 188.1999. C11H26NO requires 188.2014.
20
7.33±7.39 ,m, 2H, Ph), 7.40±7.44 ,m, 2H, Ph); [a]D
ˆ
171.6 ,c 2.7, ethanol); nmax ,liquid ®lm) 3336, 1240,
1128, 1100, 1026 cm21; HRMS ,FAB): MH1, found
272.1660. C17H22NO2 requires 272.1651.
20
,CH3)2CHO); [a]D ˆ25.0 ,c 1.9, ethanol); nmax ,liquid
4.7.11. /R)-N-/2-Methoxybenzyl)-ethylphenylglycinol /2j).
Colorless oil ,80%); 1H NMR ,400 MHz, CDCl3) d 1.18 ,t,
Jˆ7.0 Hz, 3H, CH3CH2O), 3.40±3.50 ,m, 4H, CH3CH2O
and PhCHCH2), 3.56 ,d, Jˆ13.6 Hz, 1H, ArCH2N), 3.74
,d, Jˆ13.6 Hz, 1H, ArCH2N), 3.84 ,s, 3H, CH3O), 3.91
,dd, Jˆ4.0, 9.6 Hz, 1H, PhCHCH2), 6.85±6.92 ,m, 2H,
Ar), 7.13±7.16 ,m, 1H, Ar), 7.21±7.26 ,m, 1H, Ar),
7.28±7.31 ,m, 1H, Ph), 7.33±7.38 ,m, 2H, Ph), 7.41±7.45
4.7.18. /S)-N-/2-Methoxybenzyl)-O-methylvalinol /4d).
Colorless oil ,30%); H NMR ,400 MHz, CDCl3) d 0.92
1
,t, Jˆ6.8 Hz, 6H, ,CH3)2CHC), 1.92 ,m, 1H, ,CH3)2CHC),
2.55 ,m, 1H, i-PrCHCH2), 3.85 ,s, 3H, CH3O), 3.41±3.44
,m, 2H, i-PrCHCH2), 3.82 ,m, 2H, ArCH2N), 3.32 ,s, 3H,
CH3OAr), 6.85±6.95 ,m, 2H, Ar), 7.22±7.30 ,m, 2H, Ar);
20
,m, 2H, Ph); [aD ˆ176.4 ,c 3.2, ethanol); nmax ,liquid
20
®lm) 3345, 1241, 1108 cm21; HRMS ,FAB): MH1, found
286.1794. C18H24NO2 requires 286.1807.
[a]D ˆ210.2 ,c 2.2, ethanol); nmax ,liquid ®lm) 3337,
1240, 1113, 1049, 1030 cm21; HRMS ,FAB): MH1,
found 238.1854. C14H24NO2 requires 238.1807.
4.7.12. /S)-N-Isopropyl-O-methylphenylalaninol /3a).
Colorless oil ,80%); spectral data consistent with
literature.20,22,23
4.7.19. /S)-N-/2-Methoxybenzyl)-O-ethylvalinol /4e).
Colorless oil ,60%); H NMR ,400 MHz, CDCl3) d 0.92
1
,t, Jˆ7.6 Hz, 6H, ,CH3)2CHCH), 1.19 ,t, Jˆ7.0 Hz, 3H,
CH3CH2O), 1.93 ,m, 1H, ,CH3)2CHCH), 2.56 ,m, 1H,
i-PrCHCH2), 3.38 ,m, 1H, i-PrCHCH2), 3.42±3.50 ,m,
3H, i-PrCHCH2 and CH3CH2O), 3.83 ,s. 2H, ArCH2N),
4.7.13. /S)-N-Isopropyl-O-ethylphenylalaninol /3b).
Colorless oil ,50%); H NMR ,400 MHz, CDCl3) d 1.07
,d, Jˆ6.4 Hz, 3H, ,CH3)2CHN), 1.12 ,d, Jˆ6.4 Hz, 3H,
1

J. Granander et al. / Tetrahedron 58 *2002) 4717±4725
4725
È
9. Arvidsson, P. I.; Davidsson, O.; Hilmersson, G. Tetrahedron:
Asymmetry 1999, 10, 527±534.
3.85 ,s, 3H, CH3O), 6.85±6.94 ,m, 2H, Ar), 7.21±7.30 ,m,
20
2H, Ar); [a]D ˆ28.0 ,c 2.7, ethanol); nmax ,liquid ®lm)
3321, 1241, 1120 cm21; HRMS ,FAB): MH1, found
252.1998. C15H26NO2 requires 252.1964.
10. ,a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209.
,b) Anders, E.; Koch, R.; Freunscht, P. J. Comput. Chem.
1993, 14, 1301±1312.
11. ,a) Weiss, H.; Yakimansky, A. V.; MuÈller, A. H. E. J. Am.
Chem. Soc. 1996, 118, 8897±8903. ,b) Arvidsson, P. I.;
Hilmersson, G.; Ahlberg, P. J. Am. Chem. Soc. 1999, 121,
1883±1887. ,c) Abbotto, A.; Streitwieser, A.; Schleyer,
P. v. R. J. Am. Chem. Soc. 1997, 119, 11255±11268.
12. Nakamura, E.; Nakamura, M.; Koga, N.; Morokuma, K. J. Am.
Chem. Soc. 1993, 115, 11016±11017.
Acknowledgements
Â
The authors would like to thank Mr Peter Diner for fruitful
discussions regarding the calculations. Financial support
from the Swedish Research Council ,K 5104-1292/2001)
is gratefully acknowledged.
13. ,a) Csonka, G. I. J. Comput. Chem. 1993, 14, 895±898.
,b) Nilsson Lill, S. O.; Arvidsson, P. I.; Ahlberg, P.
Tetrahedron: Asymmetry 1999, 10, 265±279.
14. PC SPARTAN pro, Version 1.0.5; Wavefunction, Inc.: 18401
Von Karman Ave., #370 Irvine, CA 92715 USA, 1995.
15. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich,
S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski,
J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A.
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