O-Methylatrolactic acid as a new reagent for determination of the enantiomeric purity and absolute configuration of chiral alcohols and amines

Article abstract of DOI:10.1016/j.tetasy.2006.05.006

Easily available in both enantiomeric forms, O-methylatrolactic acid (MAA) was successfully used as a new chiral derivatizing agent. Enantiomeric purities and the absolute configurations of chiral secondary alcohols and amines were determined using the ob

Full text of DOI:10.1016/j.tetasy.2006.05.006

Tetrahedron: Asymmetry 17 (2006) 1370–1379
O-Methylatrolactic acid as a new reagent for determination of
the enantiomeric purity and absolute configuration of chiral
alcohols and amines
*
_
Rafał Kowalczyk and Jacek Skarzewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
Received 27 March 2006; accepted 9 May 2006
Abstract—Easily available in both enantiomeric forms, O-methylatrolactic acid (MAA) was successfully used as a new chiral derivatizing
agent. Enantiomeric purities and the absolute configurations of chiral secondary alcohols and amines were determined using the observed
1
differences in H NMR chemical shifts. The Mosher’s stereochemical model explains the conformational preferences of the respective
diastereomeric MAA esters and amides. This was confirmed by the results of DFT calculations for the respective conformers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tic acid (MTPA, Mosher’s reagent)3 designed to avoid epi-
merization at the hydrogen alpha to the carbonyl, that was
problematic with the MPA derivatives.4 In the NMR spec-
tra of the thus obtained diastereomeric derivatives of CDA,
the signals coming from the new diastereotopic centers
(anisochronous) appear at the different fields (difference
in chemical shift, Dd). In order to account for the observed
sign of Dd and its value, two simple stereochemical models
were adopted by Mosher4 and Trost5 (Scheme 1). The
models were based on the anisotropy effect imposed by
Chiral a-substituted-a-arylacetic acids are known as resolv-
ing agents that allow for the separation of racemic mixtures
as well as chiral derivatizing agents (CDA), useful in the
determination of enantiomeric composition of chiral alco-
hols and amines.1 The pioneering works of Raban and
Mislow dealt with the esters and amides of O-methylman-
delic acid (MPA).2 Subsequent developments have led to
the application of a-methoxy-a-trifluoromethylphenylace-
shielding
effect
OMe
O
H
Ph OMe
Z
L2
H
H
L1
L2
Ph
H
L1
Ph
MeO
L1
MeO
L2
L1
F3C
O
O
H
Ph
O
H
L2
CF3
L2 shielded
L1 shielded
OMe
MeO Ph
L1
O
H
L1
L2
OMe
Z
Ph
L2
L1
H
H
F3C
MeO
Ph
L2
L1
H
Ph
O
H
H
CF3
L2
Z = O, NH
L1 shielded
Mosher's model for assigment of configuration
L2 shielded
Trost's model for assigment
of esters configuration
Scheme 1.
*
Corresponding author. Tel.: +48 71 320 2464; fax: +48 71 328 4064; e-mail: jacek.skarzewski@pwr.wroc.pl
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.006

R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
1371
the aryl group. They were derived empirically analyzing a
R1 R2
OH
O
H
large set of data for the diastereomeric products of known
configurations. Moreover, on this basis and with both
enantiomers of the acid in hand, it was possible to deter-
mine the absolute configurations of chiral a-amines and
alcohols.
CO2H
OCH3
R1
R2
O
DCC, DMAP
CH2Cl2,r.t., 48h
H3C
Scheme 3.
H3C OCH3
Since then, many new CDAs have been reported, including
some structural analogues of MPA.6 This allowed for the
identification of the key structural features essential for
CDA effectiveness.7 Consequently, the theoretical analysis
of the population of the respective conformers for each dia-
stereomer rationalized the essentially empirical, correlative
method.8 Despite some limited use of atrolactic acid as a
CDA,4 its O-methyl derivative, that is, O-methylatrolactic
acid 1 (MAA) has never been applied in this role. This
compound fulfills the CDA structural requirements and
its fully substituted stereogenic a-carbon center is inert to-
wards racemization. Recently, we have improved the syn-
thesis and deracemization of 19 and herein we report the
results of its application as an enantiomeric resolution re-
agent and CDA.
no acid ester hydrochloride resulted in an exactly 1:1 dia-
stereomeric mixture, as documented by GC and NMR
(see, below). The same method of MAA activation and
the reaction in the presence of pyridine was used for the
derivatization of the free amine (73% yield) with no trace
of epimerization nor kinetic resolution in the reaction of
the racemate (Scheme 2). In the case of the aminoalcohol,
this acylation method led to mixtures of the corresponding
amide and ester, which were difficult to separate chromato-
graphically. However, the aminoalcohols were selectively
N-acylated with the acyl chloride prepared from MAA
with DMF–oxalyl chloride and used under the modified
Schotten–Baumann conditions. We obtained the corre-
sponding amides in almost quantitative yield (98%) while
the corresponding crude products were pure enough for
spectral analysis.
2. Results and discussion
2.1. Derivatization
The same MAA activation method and the reaction in the
presence of pyridine was applied for the preparation of the
corresponding esters, but proved only successful for 2-
butanol. More sterically hindered hydroxy groups were
acylated (ca. 60% yield) using the DCC/DMAP method
(Scheme 3).5 As before, neither epimerization nor kinetic
resolution were observed when the reactions were carried
out with the enantiomeric or racemic substrates. Thus,
the methods adopted for the preparation of MAA amides
and esters seemed to be suitable for its use as CDA.
Firstly, in order to obtain the MAA amides from the
hydrochlorides of methyl esters of a-amino acids we used
the procedure advocated for the respective MPA amides
by Trost (DCC, DMAP, Et3N).10 However, in our case
the reaction was sluggish and the yield of the desired prod-
ucts was insufficient (ca. 20%), even after a long reaction
time. The MAA amides were successfully prepared by acti-
vating MAA with oxalyl chloride and DMF and running
the reaction in the presence of anhydrous K2CO3. (S)-
MAA and the enantiomeric amino acid derivatives gave
single diastereomeric amides (ca. 60% isolated yield).
Moreover, the reaction of (S)-MAA with the racemic ami-
2.2. Chiral discrimination: separation of diastereomers (GC)
Gas chromatography offers a simple and fast method for
the determination of enantiomeric composition.1 If an
CO2CH3
NH2xHCl
O
H
R
(S)
CO2CH3
1.DMF
2. (COCl)2
NH
H3C OCH3
R
COCl
CO2H
CH3CN, 0 °C
H3C OCH3
H3C OCH3
R3
R2
O
H
OH
NHR1
(S)
(R)
CH3
Ph
NH
H3C OCH3
K2CO3
THF/H2O, rt
O
R2
OH
N
H3C
R1
OCH3
R3
Scheme 2.

1372
R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
H3CO
Ph
HO
H
N
O
R
Ph
R
N
H
O
CO2CH3
OCH3
O
R1
2 R = iPr
8 R = CH3
9 R = Bn
3 R = CH3S(CH2)2
4 R = CH3CH2CH(CH3)
5 R = Bn
O
R2
Ph
OCH3
6 R = -CH2-3-indolyl
11 R1, R2 = CH3
12 R1 = CH3, R2 = Et
16 R1 = CH3, R2 = Ph
17 R1 = CO2CH3, R2 = Ph
O
O
Ph
N
Ph
N
H
Ph
OH
OCH3
OCH3
7
10
O
O
O
Ph
OCH3
Ph
Ph
O
O
O
OCH3
OCH3
13
14
15
Figure 1.
achiral stationary phase is used, an enantiomeric mixture
has to be derivatized with CDA into the corresponding dia-
stereomers. Separation efficiency depends mainly on the
CDA used while the influence of the stationary phase is
rather limited.12 Under these circumstances a new CDA
with nonracemizing and sterically congested stereogenic
centers are highly desirable.13 In order to test MAA in this
role we analyzed the equimolar mixtures of diastereomeric
amides prepared from the esters of a-amino acids and a-
methylbenzylamine (Fig. 1). The results are presented in
Table 1. For all the compounds analyzed the (S,S)-isomers
exhibited a weaker affinity toward the stationary phase (di-
phenyl-5%–dimethyl-95%–polysiloxane), thus a shorter
retention time was observed for them than for the respec-
tive (S,R)-isomers. The resolution factor (Rs)14 value dif-
fered in the examined cases. Thus, for amides 8–10, the
respective GC peaks were not separated completely which
could be the result of their conformational flexibility. Fur-
thermore, the diastereomeric MAA esters of chiral second-
ary alcohols differed poorly in GC while the peaks were
insufficiently separated (Rs < 1.15 and DtR < 0.50 min), ex-
cept for borneol, where DtR = 0.99 min, Rs = 1.13. More-
over, the application of the cyanopropylated (70%)
polysiloxane capillary column did not improve the separa-
tion of diastereomers. Therefore, the use of MAA as CDA
in GC is regarded as rather limited.
2.3. Chiral discrimination: quantification of enantiomers
by CDA-1H NMR
Another technique commonly used for the determination
1
of enantiomeric composition is CDA-NMR.15 In the H
NMR spectra of the diastereomeric derivatives of CDA,
the specific signals differ in chemical shift which, if not
overlapped, can be integrated individually, thus providing
information about the composition. For the MAA deriva-
tives, as for those of MPA and MTPA this possibility is of-
fered by the resonance of the corresponding methoxy
groups. To learn the scope of application of this technique
with MAA, we analyzed differences in chemical shifts
DdOMe for various diastereomeric amides and esters (Table
2). For all but 8, 12, and 13 compounds the observed dif-
ferences were far beyond the NMR spectrum accuracy lim-
it. Thus the method seemed to be suitable for the
mentioned analytical purpose. Additionally, for the amides
of methyl esters of amino acids 2–7 resonances of the ester
methyl group also differed and their integration can serve
the same aim (see below). Unfortunately, for the esters 12
and 13 the signal separation observed was insufficient
and it did not improve with a solvent change or in the pres-
ence of achiral lanthanide shift reagent Eu(fod)3. Likewise
for MAA-12, the DdOMe reported for MTPA-12 did not al-
low for its practical analytical use (DdOMe < 0.04). Other
examples (Table 2) showed that MAA, MTPA, and MPA
performed quite similarly in this respect.
Table 1. Retention times in minutes and resolution factor Rs of (S)-MAA
amides
Compound
tR1
tR2
Rsa
2
3
4
5
6
45.56 (S)
26.97 (S)
48.13 (S)
41.09 (S)
42.22 (S)
45.87 (R)
27.39 (R)
48.83 (R)
41.34 (R)
43.18 (R)
1.633
1.569
1.105
0.700
2.122
The absolute configuration of the amine was given in parentheses.
a Resolution, Rs, is defined as (tR2 ꢀ tR1)/(wh1 + wh2), where whi is a width
of a peak at a half of its height.14

R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
1373
Table 2. DdOMe values of corresponding amides and esters of MAA in
CDCl3
conformation of the amide has the methyl group coplanar
with the amide bond, as it was for CF3– in the case of the
MTPA compounds. On this basis we derived a similar
model explaining the magnetic anisotropy imposed by the
phenyl group of O-methylatrolactic acid (Scheme 4).
OMe
Compound
Dd
acid
2
3
4
5
6
7
0.074
0.072
0.030
0.110
0.136
0.071
MTPA: 0.050a
MPA: 0.038c
0.000
1
Additionally, the H NMR NOESY spectra for both dia-
stereomers of 3 corroborated this interpretation showing
the respective correlations and the absence of the other
ones (Scheme 4). If the Trost’s model (Scheme 1) was ap-
plied to the MAA derivative of the amine of known config-
uration, the resulting absolute configuration of the amine
was opposite to the real one.
8
9
0.045
10
12
0.307
0.012 (0.008)
MTPA: 0.033a (0.000)b
0.009 (0.014)
0.046 (0.041)
0.060 (0.011)
0.061 (0.100)
MTPA: 0.083a (0.100)b
0.106 (0.147)
MTPA: 0.150a (0.160)b
In order to verify the qualitative stereochemical interpreta-
tion we performed semiempirical (PM3) calculations opti-
mizing the structures of (S,S)-3 and (R,S)-3 and changing
the value of torsion angle H3CCa–C@O every 10ꢁ. Addi-
tionally, the structures close to that of the energy minimum
were further optimized. For (S,S)-3, three energy minima
structures finally resulted (the angle: 15ꢁ, 101ꢁ, and 106ꢁ)
and for (R,S)-3 two minima were observed (ꢀ1.3ꢁ and
113ꢁ). Thus the conformers obtained were subjected to
the more advanced DFT [B3LYP/6-31G (d) ꢀ DFT] calcu-
lations. For each diastereomer of 3, only two conforma-
tions were obtained (Scheme 5). Their structures differed
substantially, however only those of the lowest energy
[7.0 kcal/mol for (S,S)-3 and 5.8 kcal/mol for (R,S)-3] less
than the next ones should be taken into account. In spite
of the fact that these preferred conformations differed
somewhat from that of the Mosher’s model, in both cases
the diamagnetic influence of the phenyl group was in full
agreement with that expected within the simplified model.
13
14
15
16
17
In parentheses values obtained in CCl4 as a solvent.
a Data from Ref. 3.
b Data from Ref. 16.
c Data from Ref. 17.
2.4. MAA-derivatives applied for the determination of
absolute configuration of a-chiral alcohols and primary
amines. Stereochemical analysis
1
Thus, in the H NMR spectra of the diastereomeric deriv-
atives of enantiomeric CDA, the signals arising from the
anisochronous protons, even far removed from the stereo-
genic centers, appear at different fields (Dd). Essentially,
this effect comes from the diamagnetic influence of the aro-
matic moiety of the CDA. In order to evaluate this influ-
ence in both diastereomers of the MAA derivatives one
should consider DdS,RLn = dSLn ꢀ dRLn defined as a differ-
ence between the chemical shifts for a given proton Ln for
the (S)-MAA and (R)-MAA derivative of the same enan-
tiomeric amine or alcohol. Moreover, DdS,RLn can be ob-
tained as the difference between the chemical shift for the
(S)-MAA derivative of the (S)-amine/alcohol and the shift
for the (S)-MAA derivative of the (R)-amine/alcohol.
1
The H NMR spectrum of the isopropyl ester of MAA
demonstrated the discrimination of diastereotopic methyl
groups, Dd = 0.005 (0.082 in CCl4). Therefore, we exam-
ined the signs and values of the anisochrony for the
MAA esters of various a-chiral secondary alcohols. The
respective DdS,R values were obtained from the spectra of
(S)-MAA esters of enantiomeric and racemic alcohols,
analogously as it was done for the amides. For the enantio-
meric terpenic alcohols obtained 13–15, we analyzed the
corresponding esters of (R)- and (S)-MAA. The results
are presented in Figure 2. Unfortunately, the correspond-
ing DdS,R values (CDCl3) were smaller than those for the
MPA and MTPA derivatives.6 Furthermore, for esters
12–14, the sign of DdS,R for the hydrogens on the one side
of the ester bond plane did not differ from the sign for the
hydrogens on the opposite side of the plane (Fig. 2, under-
lined values). However, the corresponding spectra in CCl4
gave the expected distribution of the DdS,R signs, along
with an increase of their values (Fig. 2, bolded values), in
effect allowing for the determination of absolute configura-
tion of the analyzed alcohols. A solvent of decreased polar-
ity seemed to favor a conformer with the lowest dipole
moment. This conformer should give the largest contribu-
tion to the shielding/deshielding effects observed for the
respective protons. At the same time, the influence of the
other, more polar conformers should be diminished. This
reasoning is in agreement with the results of the DFT
calculations that we carried out for the MAA ester of
Thus, we calculated DdS,R values from the spectra of pure
(S,S)-amide or ester and the diastereomeric mixture of
the (S,S) and (S,R) compounds of (S)-MAA, analogously
to the Trost procedure5 (for details see Section 4). The re-
sults obtained, together with the reference data3,6,8c,18 for
the MTPA compounds are depicted on Figure 2. As can
be seen, for the amides, the observed Dd values were large
enough to distinguish both diastereomers. The signs of
DdS,R (negative or positive) were in agreement with those
noted for the MTPA analogues of the same known config-
uration (Fig. 2, 2–6). Namely, when the hydrogens on one
side of the amide bond plane gave DdS,R > 0, the hydrogens
on the opposite side of the plane gave DdS,R < 0. Therefore,
we tentatively adopted the Mosher’s stereochemical model
(Scheme 1). A comparison of the MAA derivatives with the
Mosher’s model suggested that in our case the dominating

1374
R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
-0.157 (-0.080)
-0.046 (-0.084)
-0.140 (-0.111)
-0.002 (-0.071)
O
O
0.080 (0.021)
OCH3
0.060 (0.011)
OCH3
S
-0.027(-0.112)
-0.249
NHR
NHR
(-0.180)
3
2
-0.184 (-0.126)
O
-0.060
O
(-0.082)
0.063 (0.020)
OCH3
-0.367 (-0.079)
0.071 (0.020)
OCH3
NHR
NHR
-0.166 (-0.111)
-0.174 (-0.159)
4
5
-0.103
O
(-0.070)
0.087(0.040)
0.068 (0.019)
OCH3
-0.009
0.083
OH
NHR
-0.426
NHR
NHR
N
H
-0.183 (-0.404)
7
8
6
-0,024
-0,100
NR
0.076
-0.065 0.0611 (0.057)
OH
NHR
OH
9
10
0.005
0.082
OR
-0.009 (0.110)
0.147
0.0035 (-0.080)
-0.006 (-0.090)
-0.134
OR
-0.093
0.029 (0.030)
OR
0.054
0.043
13
11
12
0.024 (-0.100)
-0.086
-0.017
-0.183
-0.075
-0.076
-0.242
OR
0,016
0.005 (0.060)
0.074
0.019 (-0.120)
OR
0.090
-0.154
-0.073
-0.080
OR
0.003 (0.030)
0.134
0.035
16
14
15
-0.003 (0.000)
-0.047
CO2CH3
OR
17
Figure 2. DdS,R values (CDCl3) for the tested MAA amides and esters. Underlined are values of unexpectedly opposite sign. Bold values are those recorded
in CCl4 solutions. In brackets, reference values (CDCl3) for the corresponding MTPA derivatives: 2–6, 9;8c 7;3 12, 16;18 13, 14;6 173 are given.
(ꢀ)-menthol (Scheme 6). There, one of two low-energy
conformers, the less polar one (calculated l = 1.48 D) dem-
onstrated a large magnetic anisotropy, while the second
one, that of higher energy (1.5 kcal/mol) and more polar

R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
1375
Table 3. Solvent effect of observed Dd values in representative amides and
esters
3.705ppm
CO2CH3
MeO
Ph
Compound
Group
CDCl3
C6D6
CS2
CCl4
OMe
Ph
H
N
NOE
(CH2)2SCH3
CO2CH3
H3CS
6
OMe
CO2CH3
C@CH
0.123
0.068
0.426
0.134
0.069
0.279
0.125
0.063
0.454
0.171
0.065
0.354
H
H3C (R)
(S)
H
CH3
1.803ppm
O
-CO2CH3 shielded
NOE
7
OMe
CH3
0.071
0.087
0.058
0.131
0.125
0.084
0.093
0.085
1.777ppm
Ph
O
SCH3
OMe
MeO
H
N
(CH2)2SCH3
CO2CH3
8
OMe
CH3
0.000
0.009
0.009
0.000
0.000
0.020
0.000
0.021
Ph
H
H3C (S)
(S) H
CO2CH3
12
OMe
CH3
CH2CH3
0.012
0.060
0.009
0.000
0.061
0.085
0.019
0.084
0.132
0.014
0.093
0.147
CH3
3.760ppm
ΔδSR CO2CH3 = 3.760-3.705 = 0.055 (> 0)
ΔδSR SCH3 = 1.777- 1.803 = - 0.026 (< 0)
-(CH2)2SCH3 shielded
17
OMe
CO2CH3
0.106
0.003
0.193
0.020
0.164
0.039
0.147
0.047
Scheme 4.
O
OCH3
H
O
OCH3
OCH3
We next examined the spectra of amides 6–8 and esters 12
and 17 in solvents less polar than CDCl3 (Table 3). For the
esters we observed an increase of the Dd values for the
MAA methoxy group as well as for the other easily identi-
fiable signals. For the amides however, the effect for DdOMe
holds on but for the other signals it was less pronounced or
even reversed.
H3C
H3CSH2CH2C
H3CSH2CH2C
H3CO
H
CH3
(S,S)-3 major conformer (1)
<H3CCα-C=O = 52°
E = -1377.40263051 a.u.
μ = 3.52 D
(S,S)-3 minor conformer (2)
<H3CCα-C=O = -152°
E = -1377.39141781 a.u.
μ = 4.68 D
Thus, the small values and non-homogeneous distribution
of the Dd signs potentially leading to mistakes in ascribing
absolute configuration can be overcome by the use of
appropriate solvent. Another difficulty arises when the
magnetic anisotropy effect of the CDA aromatic moiety
is disturbed by the influence of the additional a or b-
located polar or aryl group. In such a case the Mosher’s
model can lead to a wrong outcome.8b However, a simple
stereochemical model of Kelly (Scheme 7) relays the sign
of DdOMe of CDA to the absolute configuration of the alco-
hol analyzed.11 In this model the shielding of the CDA
methoxy group results from the influence of the alcohols
phenyl group for a like (S,S or R,R) diastereomer only,
and the absence of this effect for an unlike (S,R or R,S)
ΔE1,2 = 7.04 kcal/mol
CH3
O
O
H3CO
CO2CH3
CH3
H3CSH2CH2C
H
H3CSH2CH2C
H
H3C
H3CO
(R,S)-3 minor conformer (4)
<H3CCα-C=O = -115°
E = -1377.39518299 a.u.
μ = 4.36 D
(R,S)-3 major conformer (3)
<H3CCα-C=O = -32°
E = -1377.40443354 a.u.
μ = 3.00 D
ΔE1,2 = 5.8 kcal/mol
Scheme 5.
form. Thus, in our hands,
a
positive sign for
DdOMe ¼ duOMe ꢀ dlOMe confirmed the (S)-configuration for
2-phenylethanol (Scheme 7, A). On the other hand, in the
presence of an a-polar group, an opposite trend was ob-
served11 while the respective negative sign of DdOMe con-
firmed the (S)-configuration for the methyl ester of
mandelic acid (Scheme 7, B). The corresponding Dd values
of –OMe signals of MAA are given in Table 4.
H
OCH3
H3C
OCH3
CH3
H3C
CH3
H
(S)-(-)-14a major conformer (1)
<H3CCα-C=O = 31°
E = -1005.88153566 a.u.
μ = 1.48 D
(S)-(-)-14a minor conformer (2)
<H3CCα-C=O = -146°
E = -1005.87908916 a.u.
μ = 2.52 D
3. Conclusion
In conclusion we have developed an O-methylatrolactic
acid as a new chiral derivatizing reagent (CDA) suitable
for the determination of enantiomeric purity and absolute
configuration of chiral secondary alcohols and amines.
The Mosher’s stereochemical model explains the confor-
mational preferences of the respective diastereomeric
MAA esters and amides. This is easily available in both
enantiomeric forms, while the non-racemizing CDA sup-
plements an existing kit of such compounds.
ΔE1,2 = 1.5 kcal/mol
Scheme 6.
(calculated l = 2.52 D), was much less sensitive to the mag-
netic influence of the phenyl group. A quite similar inter-
pretation was adopted to explain the rise of the Dd values
in the less polar solutions of the MPA derivatives.8a

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R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
OCH3
Ph
CO2CH3
H
CH3
Ph
H3CO
H3C
O
O
H3CO
H
Ph
Ph
OCH3
H
H3C
O
O
H
CO2CH3
H3C
CH3
CH3
(R,S) = u
(S,S) = l
-OCH3 shielded
-OCH3 shielded
OCH3
CH3
Ph
Ph
O
CO2CH3
H3CO
H3C
O
H3C
OCH3
Ph
H
H3CO
H3C
Ph
H
O
H
O
H
CO2CH3
CH3
CH3
(S,S) = l
(R,S) = u
-OCH3 deshielded
-OCH3 deshielded
A
B
Scheme 7.
Table 4. Dd values of –OMe signals in secondary alcohols with a aromatic
moiety (see Scheme 7)
DdCOOMe (independent spectra). The mean value
Dd ¼ ð0:0667883 ꢁ 0:0000010135Þ ppm.
OMe
uꢀl
Compound
dOu Me
dOl Me
Dd
Configuration
16
3.315
3.114
3.254
3.015
0.061
0.099
S
Computational methods: The theoretical studies supporting
the search for the low-energy conformers were performed
applying semiempirical PM3 (GAUSSIAN-03) method. Thus
the emerged structures were further optimized using the
density functional theory (DFT) method. The DFT ap-
proach utilized Backe’s three-parameter functional22 with
the local correlation part of Vosco et al.23 and the non-lo-
cal part of Lee et al.24 (abbreviated as B3LYP). The calcu-
lation were performed in the standard 6-13G* atomic basis
set.25 The enthalpy differences were calculated for the the-
oretically optimized structures. The results reported here
were obtained using the GAUSSIAN-03 package.26 The calcu-
lations were performed at the Wroclaw Center for Net-
working and Supercomputing.
17
3.318
3.108
3.424
3.256
ꢀ0.106
ꢀ0.147
S
Bolded values obtained from CCl4 as a solvent.
4. Experimental
4.1. General methods
All commercially available materials were used without
purification. The methyl ester of (S)-mandelic acid,19
(ꢀ)-cis-caran-trans-4-ol20 and the hydrochlorides of methyl
ester of amino acids21 were prepared according to the liter-
ature procedures. 1H NMR spectra of the samples in
CDCl3 (ca. 5–8 mg in 0.5 ml) were recorded using a Bruker
CPX (1H, 300 MHz) and Bruker Avance II (600 MHz)
spectrometer and the chemical shifts (ppm) were internally
referenced to the TMS signal. GC analyses were carried out
4.2. General method for the preparation of diastereomeric
amides from (S)-O-methylatrolactic acid and
corresponding amines
Method A. Oxalyl chloride (26 ll, 0.30 mmol, 1.1 equiv)
was added slowly to a mixture of DMF (32 ll, 0.42 mmol,
1.5 equiv) in CH3CN (0.5 ml) and stirred vigorously on an
ice-water bath. Then, to the resulting suspension, a solu-
tion of MAA (50 mg, 0.28 mmol, 1 equiv) in CH3CN
(1.0 ml) was added dropwise via syringe. The mixture was
stirred for 15 min at 0 ꢁC, and then K2CO3 (116 mg,
0.83 mmol, 3 equiv) was added followed by the portionwise
addition of the corresponding hydrochloric salt of amino
acid methyl ester (0.30 mmol, 1.1 equiv) for 1 h. After 4 h
at 0 ꢁC the suspension was quenched with ether (20 ml),
washed with water (10 ml), dried over Na2CO3, and
evaporated. The products were purified by column
chromatography on silica gel eluting with PET–AcOEt
(4:1, v/v).
on
a Hewlett–Packard 5890 II gas chromatograph
(HP5MS 30m capillary column) or a Shimadzu GC-17A
gas chromatograph (BPX 70 25 m capillary column). Melt-
ing points were measured using a Boetius hot-stage appara-
tus and are uncorrected. IR spectra were recorded on a
Perkin–Elmer 1600 FTIR spectrophotometer. High resolu-
tion mass spectra were recorded on a Finnigan MAT 95
spectrometer operating on the electron impact (EI, 70 eV)
or chemical ionization (CI, isobutane) mode. Observed
rotations at 589 nm were measured using an Optical Activ-
ity Ltd. Model AA-5 automatic polarimeter. Separations
of products by chromatography were performed on silica
gel 60 (230–400 mesh) purchased from Merck. Thin layer
chromatography analyses were performed using silica gel
60 precoated plates (Merck).
Method B. In this method, the active acylating agent was
generated as mentioned above in method A. After the acid
chloride preparation step, a solution of (R)-a-methylbenz-
The reproducibility of the chemical shift difference was ver-
ified for 6. We measured six independent values of

R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
1377
ylamine (0.078 ml, 0.061 mmol, 1.1 equiv) in pyridine
(2 equiv) was added in one portion via syringe and the
resulting mixture stirred for 1 h, diluted with ether
(25 ml), washed with aqueous CuSO4 (satd, 2 · 8 ml), dried
over MgSO4, and evaporated. The crude product was puri-
fied as above.
4.2.4. (2S,3S)-2-((S)-2-Methoxy-2-phenyl-propionylamino)-
3-methyl-pentanoic acid methyl ester 4. Colorless oil;
Rf = 0.39 (PET–AcOEt, 4:1, v/v); [a]D = +35.8 (c 0.30,
CH2Cl2); IR (film): m 3424, 2964, 2879, 1742, 1685, 1507,
1449, 1245, 1210, 1152, 1072, 730, 699 cmꢀ1 1H NMR
;
(CDCl3): d 7.46 (2H, dd, J = 7.0, 1.8 Hz, o-ArH), 7.24–
7.37 (4H, m, ArH and NH), 4.52 (1H, dd, J = 9.0,
5.0 Hz, CH), 3.77 (3H, s, CO2CH3), 3.27 (3H, s, OMe),
1.79–1.89 (1H, m, CH), 1.78 (3H, s, Me), 1.34 (1H, m,
CHAHB), 1.08 (1H, m, CHAHB), 0.84 (3H, t, J = 7.4 Hz,
Me), 0.78 (3H, d, J = 6.9 Hz, Me); 13C NMR (CDCl3): d
173.3, 172.4, 141.1, 128.3, 127.7, 125.9, 82.0, 56.0, 51.9,
51.3, 37.9, 25.0, 20.2, 15.4, 11.4; HRMS (EI): m/z [M+]
calcd for C17H25NO4: 307.1784. Found: 307.1781.
Method C. The acid chloride generated as it was described
in method A (0.41 mmol, 1.5 equiv) in anhydrous THF
(2 ml) was added dropwise at room temperature to the vig-
orously stirred mixture of corresponding aminoalcohol
(0.28 mmol, 1 equiv) and K2CO3 (172 mg, 1.2 mmol,
4.5 equiv) in water (3 ml). The resulted yellow solution
was stirred for 48 h diluted with diethyl ether (10 ml), the
phases were separated and the aqueous layer was washed
with ether (10 ml). The combined organic layers were dried
over Na2CO3 and the solvent evaporated to give the pure
product (>98%, GC).
4.2.5.
(S)-2-((S)-2-Methoxy-2-phenyl-propionylamino)-3-
phenyl-propionic acid methyl ester 5. Colorless oil;
Rf = 0.29 (PET–AcOEt, 4:1, v/v); [a]D = +98.7 (c 1.14,
CH2Cl2); IR (film): m 3029, 2950, 2834, 1744, 1682, 1507,
4.2.1.
(S)-2-((S)-2-Methoxy-2-phenyl-propionylamino)-4-
1444, 1217, 1199, 1143, 1073, 733, 699 cmꢀ1 1H NMR
;
methyl-pentanoic acid methyl ester 2. Colorless oil;
Rf = 0.38 (PET–AcOEt, 4:1, v/v); [a]D = +12.7 (c 0.88,
CH2Cl2); IR (film): m 3357, 3061, 2957, 2872, 2835, 1745,
1683, 1510, 1446, 1368, 1273, 1205, 1159, 1072, 1047,
(CDCl3): d 7.14–7.37 (10H, m, ArH), 6.87 (1H, br s,
NH), 4.84 (1H, m, CH), 3.74 (3H, s, CO2CH3), 3.21 (3H,
s, OMe), 2.97–3.10 (2H, m, CH2), 1.76 (3H, s, Me); 13C
NMR (CDCl3): d 173.1, 172.0, 141.0, 135.8, 129.3, 128.4,
128.3, 127.7, 126.9, 126.0, 81.9, 52.8, 55.3, 51.3, 37.8,
20.4; HRMS (EI): m/z [M+] calcd for C20H23NO4:
341.1627. Found: 341.1621.
732, 700 cmꢀ1
;
1H NMR (CDCl3): d 7.45 (2H, d,
J = 7.2 Hz, o-ArH), 7.30–7.36 (3H, m, ArH), 7.18 (1H,
br d, J = 7.4 Hz, NH), 4.57 (1H, m, CH), 3.74 (3H, s,
CO2CH3), 3.27 (3H, s, OMe), 1.78 (3H, s, Me), 1.41–1.67
(3H, m, CH2 and CH(CH3)2), 0.79–0.86 (6H, m, 2 · Me);
13C NMR (CDCl3): d 173.5, 173.4, 141.0, 128.3, 127.8,
125.9, 81.9, 52.2, 51.3, 50.4, 41.5, 24.8, 22.8, 21.7, 20.3;
HRMS (EI): m/z [M+] calcd for C17H25NO4: 307.1784.
Found: 307.1794.
4.2.6. (S)-3-(1H-Indol-3-yl)-2-((S)-2-methoxy-2-phenyl-pro-
pionylamino)-propionic acid methyl ester 6. Colorless
solid; Rf = 0.17 (CHCl3); [a]D = +75.6 (c 0.24, CH2Cl2);
1
IR (CCl4): m 3490, 3423, 1748, 1686, 1512, 1215 cmꢀ1; H
NMR (CDCl3): d 7.92 (1H, br s, indole-NH), 7.46 (1H,
d, J = 7.8 Hz, ArH), 7.28–7.38 (7H, m, ArH and NH),
7.18 (1H, dt, J = 7.4, 0.9 Hz, ArH), 7.11 (1H, dt, J = 7.4,
0.9 Hz, ArH), 6.57 (1H, d, J = 2.2 Hz, C@CH), 4.89 (1H,
m, CH), 3.69 (3H, s, CO2CH3), 3.23 (2H, m, CH2), 3.17
(3H, s, OMe), 1.75 (3H, s, Me); 13C NMR (CDCl3): d
173.2, 172.4, 141.3, 130.0, 128.3, 127.6, 127.5, 126.0,
122.9, 122.1, 119.6, 118.6, 111.1, 109.9, 81.9, 52.4, 52.3,
51.3, 27.6, 20.5; HRMS (EI): m/z [M+] calcd for
C22H24N2O4: 380.1736. Found: 380.1738.
4.2.2.
(S)-2-((S)-2-Methoxy-2-phenyl-propionylamino)-4-
methylsulfanyl-butyric acid methyl ester 3a. Colorless oil;
Rf = 0.26 (PET–AcOEt, 4:1, v/v); [a]D = +36.4 (c 0.84,
CH2Cl2); IR (film): m 2982, 2952, 2916, 2834, 1744, 1681,
1510, 1444, 1366, 1222, 1173, 1072, 1047, 732, 700,
1
670 cmꢀ1; H NMR (CDCl3): d 7.38–7.47 (3H, m, ArH
and NH), 7.24–7.37 (3H, m, ArH), 4.62–4.69 (1H, m,
CH), 3.76 (3H, s, CO2CH3), 3.27 (3H, s, OMe), 2.26–2.32
(2H, m, SCH2), 2.07–2.17 (1H, m, SCH2CHAHB), 1.95
(3H, s, Me), 1.85–1.94 (1H, m, SCH2CHAHB), 1.78 (3H,
s, SCH3); 13C NMR (CDCl3): d 173.5, 172.3, 141.2,
128.4, 127.8, 125.8, 82.0, 52.5, 51.4, 51.1, 31.9, 29.8, 20.2,
15.4; HRMS (EI): m/z [M+] calcd for C16H23NSO4:
325.1348. Found: 325.1354.
4.2.7. (S)-2-Methoxy-2-phenyl-N-((R)-1-phenyl-ethyl)-pro-
pionamide 7. Colorless oil; Rf = 0.32 (PET–AcOEt, 4:1,
v/v); [a]D = +130.3 (c 0.26, CH2Cl2); IR (film): m 3332,
1
3069, 2981, 1936, 1677, 1507, 1149, 1072, 699 cmꢀ1; H
NMR (CDCl3): d 7.39 (2H, d, J = 6.9 Hz, o-ArH), 7.24–
7.34 (7H, m, ArH), 7.19 (1H, t, J = 7.6 Hz, ArH), 7.13
(1H, br d, J = 7.5 Hz, NH), 5.07 (1H, m, CH), 3.22 (3H,
s, OMe), 1.81 (3H, s, Me), 1.53 (3H, d, J = 6.9 Hz, Me);
13C NMR (CDCl3): d 172.5, 142.2, 140.2, 128.5, 128.3,
127.7, 127.1, 126.2, 126.0, 82.0, 51.2, 48.2, 21.8, 20.3;
HRMS (EI): m/z [M+] calcd for C18H21NO2: 283.1572.
Found: 283.1579.
4.2.3.
(S)-2-((R)-2-Methoxy-2-phenyl-propionylamino)-4-
methylsulfanyl-butyric acid methyl ester 3b. Colorless oil;
Rf = 0.26 (PET–AcOEt, 4:1, v/v); [a]D = ꢀ28.6 (c 0.86,
CH2Cl2); IR (film): m 3406, 3052, 2977, 2951, 2833, 1743,
1680, 1511, 1444, 1367, 1225, 1196, 1148, 1071, 733,
1
700 cmꢀ1; H NMR (CDCl3): d 7.51 (1H, br s, NH), 7.46
(2H, d, J = 7.2 Hz, o-ArH), 7.27–7.37 (3H, m, ArH),
4.60–4.67 (1H, m, CH), 3.70 (3H, s, CO2CH3), 3.20 (3H,
s, OMe), 2.53 (2H, t, J = 7.5 Hz, SCH2), 1.99–2.33 (2H,
m, SCH2CH2), 2.11 (3H, s, SCH3), 1.80 (3H, s, Me); 13C
NMR (CDCl3): d 173.5, 172.1, 140.1, 128.3, 127.9, 126.5,
81.8, 52.4, 51.3, 51.1, 31.9, 30.1, 20.3, 15.5.
4.2.8. (R)-2-Aminopropanol-(R)-O-methylatrolactic acid
amide 8. Colorless oil; Rf = 0.13 (CHCl3); [a]D = ꢀ39.7
(c 1.36, CH2Cl2); IR (film): m 3417, 2974, 2933, 2832,
1665, 1526, 1448, 1369, 1229, 1135, 733, 700 cmꢀ1 1H
;
NMR (CDCl3): d 7.37 (2H, dd, J = 6.9, 1.6 Hz, o-ArH),

1378
R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
7.17–7.29 (4H, m, ArH and NH), 3.79 (1H, m, CH), 3.30
(1H, m, CHAHB), 3.13 (3H, s, OMe), 3.06 (1H, m,
CHAHB), 2.60 (1H, br s, OH), 1.72 (3H, s, Me), 1.06
(3H, d, J = 6.3 Hz, Me); 13C NMR (CDCl3): d 174.7,
140.7, 128.4, 127.8, 126.2, 81.9, 67.3, 51.1, 46.8, 20.8,
20.4; HRMS (EI): m/z [M+] calcd for C13H19NO3:
237.1365. Found: 237.1372.
(c 0.76, CH2Cl2); IR (film): m 2938, 2975, 1728, 1450,
1
1257, 1109, 699 cmꢀ1; H NMR (CDCl3): d 7.48 (2H, m,
o-ArH), 7.25–7.37 (3H, m, ArH), 4.85–4.95 (1H, m, CH),
3.31 (3H, s, OMe), 1.78 (3H, s, Me), 1.54 (2H, m, CH2),
1.17 (3H, d, J = 6.3 Hz, Me), 0.78 (3H, t, J = 7.3 Hz,
Me); 13C NMR (CDCl3): d 172.1, 141.2, 128.2, 127.7,
125.8, 81.8, 73.4, 52.0, 28.7, 22.1, 22.0, 19.3; HRMS (CI):
m/z [M+H+] calcd for C14H21O3: 237.1491. Found:
237.1488.
4.2.9. (S)-Phenylalanin-2-ol-(R)-O-methylatrolactic acid
amide 9. Colorless crystals; mp 132–133 ꢁC; [a]D = ꢀ43.0
(c 0.64, CH2Cl2); IR (KBr): m 3398, 3368, 2930, 1649,
4.3.3. (ꢀ)-Bornyl-(S)-O-methylatrolactate 13a. Colorless
oil; Rf = 0.52 (hexane–AcOEt, 10:1, v/v); [a]D = ꢀ37.9
(c 0.83, CH2Cl2); IR (film): m 2954, 2831, 1733, 1453,
1522, 1458, 1151, 1097, 1046, 955, 731, 700 cmꢀ1 1H
;
NMR (CDCl3): d 7.34 (2H, dd, J = 8.3, 1.9 Hz, ArH),
7.11–7.29 (8H, m, ArH), 7.04 (1H, br d, J = 7.4 Hz, NH),
3.98–4.01 (1H, m, CH), 3.56 (1H, m, AB-system, J = 11.1,
3.5 Hz, CHAHB), 3.47 (1H, m, AB-system, J = 11.1,
5.5 Hz, CHAHB), 2.99 (3H, s, OMe), 2.86 (1H, m, AB-sys-
tem J = 13.9, 7.0 Hz, CHAHB), 2.75 (1H, m, AB-system
J = 13.9, 8.0 Hz, CHAHB), 2.69 (1H, br s, OH), 1.61 (3H,
s, Me); 13C NMR (CDCl3): d 174.2, 140.9, 137.9, 127.3,
128.5, 128.4, 127.8, 126.6, 125.7, 81.9, 64.1, 52.9, 51.7,
41.4, 19.5; HRMS (EI): m/z [M+] calcd for C19H23NO3:
313.1678. Found: 313.1674.
1256, 1120 cmꢀ1 1H NMR (CDCl3): d 7.50 (2H, d,
;
J = 7.7 Hz, o-ArH), 7.36 (2H, t, J = 7.7 Hz, m-ArH),
7.27–7.33 (1H, m, p-ArH), 4.90 (1H, m, CH), 3.32 (3H, s,
OMe), 2.24–2.35 (1H, m, CH), 1.81 (3H, s, Me), 1.61–
1.81 (3H, m, CH and CH2), 1.18–1.27 (1H, m, CH),
1.00–1.10 (1H, m, CH), 0.88 (3H, s, Me), 0.84 (3H, s,
Me), 0.78–0.84 (1H, m, CH), 0.75 (3H, s, Me); 13C NMR
(CDCl3): d 173.0, 141.1, 128.2, 127.8, 126.0, 81.7, 80.8,
52.1, 48.9, 47.8, 44.9, 36.4, 27.9, 27.1, 21.8, 19.6, 18.9,
13.4; HRMS (EI): m/z [M+] calcd for C20H28O3:
316.2038, Found: 316.2034.
4.2.10. (ꢀ)-Ephedrine-(R)-O-methylatrolactic acid amide
10. Sticky colorless oil; Rf = 0.25 (CHCl3); [a]D = +3.4
(c 0.76, CH2Cl2); IR (film): m 3417, 3061, 3029, 2990,
2935, 1620, 1490, 1450, 1401, 1369, 1257, 1193, 1125,
4.3.4. (ꢀ)-Bornyl-(R)-O-methylatrolactate 13b. Colorless
oil; Rf = 0.48 (hexane–AcOEt, 10:1, v/v); [a]D = ꢀ11.1
(c 0.92, CH2Cl2); IR (film): m 2593, 2828, 1730, 1452,
1075, 1046, 765, 736, 702 cmꢀ1
;
1H NMR (CDCl3): d
1372, 1256, 1120, 763, 699 cmꢀ1 1H NMR (CDCl3): d
;
7.07–7.34 (10H, m, ArH), 4.74 (1H, m, CHOH), 4.49
(1H, m, NCH), 3.59 (1H, br s, OH), 3.23 (3H, s, OMe),
2.39 (3H, s, NMe), 1.50 (3H, s, Me), 1.18 (3H, d,
J = 7.0 Hz, Me); 13C NMR (CDCl3): d 172.9, 143.8,
141.6, 128.35, 128.29, 127.7, 126.9, 126.8, 123.8, 83.8,
77.1, 57.3, 51.5, 32.5, 26.2, 12.6; HRMS (CI):
m/z [M+H+] calcd for C20H26NO3: 328.1913. Found:
328.1916.
7.80 (2H, dd, J = 8.3, 1.4 Hz, o-ArH); 7.35 (2H, m,
m-ArH), 7.29 (1H, m, p-ArH), 4.86–4.91 (1H, m, CH),
3.31 (3H, s, OMe), 2.26–2.38 (1H, m, CH), 1.81 (3H, s,
Me), 1.67–1.79 (2H, m, 2 · CH), 1.64 (1H, d, J = 4.1 Hz,
CH), 1.15–1.27 (1H, m, CH), 1.04–1.11 (1H, m, CH),
0.88 (3H, s, Me), 0.84 (3H, s, Me), 0.78–0.81 (1H, m,
CH), 0.71 (3H, s, Me); 13C NMR (CDCl3): d 173.1,
141.1, 128.2, 127.8, 126.0, 81.7, 80.9, 52.1, 48.8, 47.8,
44.8. 36.7, 27.9, 27.0, 21.7, 19.6, 18.9, 13.4.
4.3. Preparations of the diastereomeric esters from the
corresponding alcohols and O-methylatrolactic acid
4.3.5. (ꢀ)-Menthyl-(S)-O-methylatrolactate 14a. Color-
less oil; Rf = 0.47 (hexane–AcOEt, 10:1, v/v);
[a]D = ꢀ73.3 (c 0.63, CH2Cl2); IR (film): m 2953, 2869,
Preparations of the diastereomeric esters from the corre-
sponding alcohols and O-methylatrolactic acid were car-
ried out with DCC–DMAP according to the procedure
described by Trost5 and the products were purified by col-
umn chromatography on silica gel eluting with PET–
AcOEt (20:1.5, v/v).
1728, 1454, 1254, 1120, 769, 726, 698 cmꢀ1 1H NMR
;
(CDCl3): d 7.48 (2H, d, J = 7.0 Hz, o-ArH), 7.27–7.36
(3H, m, ArH), 4.71 (1H, dt, J = 10.9, 4.3 Hz, CH), 3.32
(3H, s, OMe), 1.94 (1H, m, CH), 1.77 (3H, s, Me), 1.64
(2H, m, CH2); 1.47–1.57 (2H, m, CH2), 1.27–1.40 (1H,
m, CH); 0.84–1.07 (3H, m, CH2 and CH), 0.88 (3H, d,
J = 6.5 Hz, Me), 0.74 (3H, d, J = 6.9 Hz, Me), 0.59 (3H,
d, J = 6.9 Hz, Me); 13C NMR (CDCl3): d 172.5, 141.4,
128.1, 127.7, 125.6, 81.9, 75.4, 52.1, 46.9, 40.5, 34.2, 31.4,
25.7, 23.0, 22.2, 22.0, 20.7, 15.8; HRMS (EI): m/z [M+]
calcd for C20H30O3: 318.2195. Found 318.2194.
4.3.1. (R)-Propan-2-ol-O-methylatrolactate 11. Colorless
oil; Rf = 0.34 (hexane–AcOEt, 10:1, v/v); [a]D = +24.4 (c
0.31, CH2Cl2); IR (film): m 2984, 2937, 1729, 1451, 1374,
1260, 1140, 1103, 699 cmꢀ1 1H NMR (CDCl3): d 7.48
;
(2H, dd, J = 7.2, 1.5 Hz, o-ArH), 7.28–7.38 (3H, m,
ArH), 5.07 (1H, h, J = 6.2 Hz, –CH(CH3)2), 3.30 (3H, s,
OMe), 1.77 (3H, s, Me), 1.20 (6H, two d, J = 6.2 Hz,
2 · Me); 13C NMR (CDCl3): d 172.5, 141.1, 128.2, 127.8,
125.9, 81.7, 68.2, 52.0, 22.2, 21.6; HRMS (CI): m/z
[M+H+] calcd for C13H19O3: 223.1330. Found: 223.1334.
4.3.6. (ꢀ)-Menthyl-(R)-O-methylatrolactate 14b. Color-
less oil; Rf = 0.42 (hexane–AcOEt, 10:1, v/v); [a]D = ꢀ49.5
(c 1.10, CH2Cl2); IR (film): m 3061, 2955, 2870, 1727, 1452,
1
1252, 1136, 1117, 776, 729, 698 cmꢀ1; H NMR (CDCl3):
d 7.47 (2H, d, J = 6.9 Hz, o-ArH), 7.28–7.40 (3H, m,
ArH), 4.36 (1H, dt, J = 10.8, 4.3 Hz, CH), 3.28 (3H, s,
OMe), 1.95 (1H, m, CH), 1.79 (3H, s, Me), 1.57–1.67 (2H,
4.3.2. (R)-sec-Butyl-(S)-O-methylatrolactate 12. Colorless
oil; Rf = 0.52 (hexane–AcOEt, 10:1, v/v); [a]D = +40.4

R. Kowalczyk, J. Skarz_ewski / Tetrahedron: Asymmetry 17 (2006) 1370–1379
1379
m, CH2), 1.39–1.47 (2H, m, CH2), 1.30 (1H, m, CH), 0.79–
Acknowledgements
1.01 (3H, m, CH2 and CH), 0.88 (3H, d, J = 6.4 Hz, Me),
0.72 (3H, d, J = 6.9 Hz, Me), 0.57 (3H, d, J = 6.9 Hz,
Me); 13C NMR (CDCl3): d 172.5, 140.8, 128.2, 127.8,
126.1, 81.5, 75.3, 51.9, 46.9, 40.5, 34.2, 31.4, 26.6, 23.0,
22.0, 21.4, 20.7, 15.7.
We are grateful to the Ministry of Education and Science
for financial support (Grant KBN Nr. 3 T09A 132 28).
References
4.3.7. (ꢀ)-cis-Caran-trans-4-yl-(S)–O-methylatrolactate 15a.
Colorless oil; Rf = 0.55 (hexane–AcOEt, 10:1, v/v);
[a]D = ꢀ74.2 (c 0.90, CH2Cl2); IR (film): m 3062, 2988,
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2936, 1728, 1451, 1256, 1122, 771, 727, 698 cmꢀ1 1H
;
NMR (CDCl3): d 7.40 (2H, dd, J = 7.7, 1.2 Hz, o-ArH),
7.17–7.29 (3H, m, ArH), 4.32 (1H, m, CH), 3.24 (3H, s,
OMe), 1.83–2.01 (2H, m, CH2), 1.69 (3H, s, Me), 1.43–
1.54 (1H, m, CH), 1.30–1.42 (1H, m, CH), 0.87 (6H, s,
2 · Me), 0.73–0.84 (1H, m, CH), 0.54–0.66 (2H, m,
2 · CH), 0.55 (3H, d, J = 6.4 Hz, Me); 13C NMR (CDCl3):
d 172.7, 141.3, 128.2, 127.7, 125.8, 81.8, 78.7, 52.0, 33.6,
28.7, 28.3, 26.4, 22.1, 21.3, 20.0, 17.7, 17.5, 15.9; HRMS
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4.3.8. (ꢀ)-cis-Caran-trans-4-yl-(R)-O-methylatrolactate 15b.
Colorless oil; Rf = 0.55 (hexane–AcOEt, 10:1, v/v);
[a]D = ꢀ42.3 (c 1.03, CH2Cl2); IR (film): m 3062, 2988,
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1
2938, 2867, 1728, 1450, 1254, 1135, 11217, 699 cmꢀ1; H
NMR (CDCl3): d 7.45–7.49 (2H, m, o-ArH), 7.25–7.37
(3H, m, ArH), 4.36 (1H, m, CH), 3.30 (3H, s, OMe), 2.06
(1H, m, CH), 1.91–1.99 (1H, m, CH), 1.77 (3H, s, Me),
1.48–1.53 (1H, m, CH), 1.41–1.47 (1H, m, CH), 0.955
and 0.948 (6H, two s, 2 · Me), 0.80–0.91 (1H, m, CH),
0.62–0.73 (2H, m, 2 · CH), 0.54 (3H, d, J = 6.5 Hz, Me);
13C NMR (CDCl3): d 172.9, 141.0, 128.2, 127.8, 126.0,
81.7, 78.8, 52.1, 33.5, 28.7, 28.3, 26.4, 21.9, 21.2, 20.0,
17.72. 17.66, 16.0.
_
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4.3.9. (S)-1-Phenylethyl-(S)-O-methylatrolactate 16. Col-
orless oil; Rf = 0.36 (hexane–AcOEt, 10:1, v/v);
[a]D = ꢀ44.2 (c 0.75, CH2Cl2); IR (film): m 3062, 2984,
1732, 1494, 1451, 1249, 1127, 1055, 763, 698 cmꢀ1 1H
;
NMR (CDCl3): d 7.44 (2H, dd, J = 8.0, 1.7 Hz, o-ArH),
7.25–7.33 (6H, m, ArH), 7.17–7.19 (2H, m, ArH), 5.92
(1H, q, J = 6.6 Hz, CH(CH3)Ph), 3.25 (3H, s, OMe), 1.80
(3H, s, Me), 1.48 (3H, d, J = 6.6 Hz, Me); 13C NMR
(CDCl3): d 172.2, 141.2, 140.8, 128.4, 128.3, 127.9, 127.8,
126.1, 126.0, 81.7, 73.2, 52.1, 22.0, 21.98; HRMS (CI): m/
z [M+H+] calcd for C18H21O3: 285.1491. Found: 285.1488.
4.3.10. (S)-Methylmandelate-(S)-O-methylatrolactate 17.
Colorless oil; Rf = 0.24 (hexane–AcOEt, 10:1, v/v);
[a]D = +61.3 (c 1.05, CH2Cl2); IR (film): m 3063, 2992,
2951, 2837, 1749, 1495, 1450, 1222, 1113, 1033, 768, 734,
1
698 cmꢀ1; H NMR (CDCl3): d 7.57 (2H, d, J = 7.0 Hz,
o-ArH), 7.30–7.38 (8H, m, ArH), 5.94 (1H, s, CH), 3.68
(3H, s, CO2CH3), 3.42 (3H, s, OMe), 1.84 (3H, s, Me);
13C NMR (CDCl3): d 172.6, 169.0, 140.5, 133.5, 129.2,
128.7, 128.3, 128.0, 127.4, 126.1, 81.8, 75.1, 52.6, 52.5,
22.7; HRMS (CI): m/z [M+H+] calcd for C19H21O5:
329.1389. Found: 329.1397.
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