N-(Chloroacetyl)- and N-(dichloroacetyl)-N-(xylyl)alanine esters: Assignment of the absolute configurations and enantiodifferentiation by the dirhodium method

Article abstract of DOI:10.1016/j.tetasy.2005.06.008

Four chlorinated N-acylalanine methylesters (metalaxyl derivatives) containing either stereogenic centres alone as in 1 and 3 or stereogenic centres plus chiral axes as in 2 and 4 were investigated. The latter have been examined in terms of the absolute c

Full text of DOI:10.1016/j.tetasy.2005.06.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2285–2293
N-(Chloroacetyl)- and N-(dichloroacetyl)-N-(xylyl)alanine
esters: assignment of the absolute configurations and
enantiodifferentiation by the dirhodium method
a
b
b,c
Edison Dıaz Gomez, Jorge Jios, Carlos O. Della Vedova, Hugo D. March,d
´
´
´
d
e
e
a
a
´
´
´
Hector E. Di Loreto, Gabor Toth, Andras Simon, Dieter Albert, Stefan Moeller,
Rudolf Wartchowf and Helmut Duddecka,*
aHannover University, Institute of Organic Chemistry, Schneiderberg 1B, D-30167 Hannover, Germany
b
´
´
Laboratorio de Servicios a la Industria y al Sistema Cientıfico (UNLP-CIC-CONICET), Departamento de Quımica, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata, 47 esq. 115 (1900) La Plata, Argentina
cCEQUINOR (CONICET, UNLP), Universidad Nacional de La Plata, La Plata, Argentina
d
´
IPESA S.A. Laboratories, Joaquın V. Gonzalez 4977, Buenos Aires, Argentina
Institute for General and Analytical Chemistry of the Budapest University of Technology and Economics, Szent Gellert ter 4,
e
´
´
H-1111 Budapest, Hungary
fHannover University, Institute of Inorganic Chemistry, Callinstr. 9, D-30167 Hannover, Germany
Received 10 May 2005; accepted 2 June 2005
´ ´
This work is dedicated to Professor Andras Liptak, Hungarian Academy of Science, Carbohydrate Research Group, Debrecen, Hungary, on the
occasion of his 70th birthday.
Abstract—Four chlorinated N-acylalanine methylesters (metalaxylꢀ derivatives) containing either stereogenic centres alone as in 1
and 3 or stereogenic centres plus chiral axes as in 2 and 4 were investigated. The latter have been examined in terms of the absolute
configurations of the diastereomers in unresolvable mixtures, which were determined by evaluating NOE contacts in preferred con-
formations. Although these ligands are weak donors in Rh* adducts, it is easily possible to monitor their enantiomeric purity by the
Ôdirhodium methodÕ. Surprisingly, only the monochloro derivatives 1 and 2 gave satisfactory results in chirality recognition exper-
iments under standard dirhodium method conditions (including one drop of acetone-d6 for enhancing the solubility of Rh*). The
dichloro derivatives 3 and 4 failed. However, they developed significant dispersion effects in the absence of acetone-d6. It turns
out that the preferred complexation site in the monochloro derivatives 1 and 2 is primarily the amide carbonyl oxygen, whereas this
group is hardly available in the case of the dichloro derivatives 3 and 4 so that the ester group appears to be the complexation site.
ꢁ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
axyl-Mꢀ, is the biologically most active agent against
fungi whereas the (S)-isomer shows very low biological
activity.
Alanine esters 1–4 belong to the acylaniline family and
are derivatives of metalaxylꢀ whose structure is similar
to that of 1 (Scheme 1) with the chlorine atom in 1
replaced by OCH3. Metalaxylꢀ is a fungicide used for
seed, soil or foliar treatment against fungi of the Peron-
osporales order, and was placed on the market by Ciba-
Geigy in 1977.1 Moser and Vogel2 and Hubele et al.3
reported that the (R)-enantiomer, also known as Metal-
Halogenated derivatives have also been prepared4 and
shown to possess fungicidal properties as well.5 It has
been claimed that the transoid orientation of the xylyl
ring and the amide carbonyl group (cf. Fig. 1) is essen-
tial for the activity.6 Hence, a detailed stereochemical
and spectroscopic analysis of alanine esters 1–4 (Scheme
1) appeared desirable.
*
Over the last decade, the dirhodium method of chirality
recognition has been introduced in which the chiral
Corresponding author. Tel.: +49 511 762 4615; fax: +49 511 762
4616; e-mail: duddeck@mbox.oci.uni-hannover.de
0957-4166/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.008

´ ´
E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2286
case of some xanthine derivatives.10 Therefore, we were
6
1COOCH3
O
C 4
R
O
interested in extending this method to other multifunc-
tional hard-base compounds and decided to investigate
title compounds 1–4 as prototypes for the important
acylamino acid/acylaniline family having at least three
possible binding sites, two carbonyl oxygens and one
nitrogen atom.
2CH
X
3
5
R
O
CH3
O
CH
O
N
Cl
7C´ H3
R9´
1´
Rh
Rh
O
O
2´
6´
O
O
R
3´
5´
4´
Rh*
R
2. Results and discussion
R8´
2.1. Stereochemical and NMR signal assignment of the
alanine ester derivatives 1–4
1
2
3
4
OCH3
X
H
H
H
CH3
Cl Cl
CH3
C
R =
Ph
CF3
R8´
The 1H and 13C chemical shifts of compounds 1–4,
assigned on the basis of their DEPT, COSY, HMQC
and HMBC spectra, are listed in Table 1. Compounds
1–4 all possess a stereogenic centre (a carbon of the ala-
nine, C-2), the absolute configuration of which is known
from their synthesis (cf. Experimental, Section 4.1). The
molecules possess a high barrier in the rotation of the
bond between the nitrogen and the aryl group (atrop-
isomerism) giving rise to an additional chirality axis in
2 and 4. This has already been discussed for a number
of similarly substituted anilines, among them alanine11
and metalaxylꢀ derivatives.12 Thus, 1 and 3—with their
symmetrical xylyl group (20,60-dimethylphenyl)—exist as
enantiomeric mixtures with pairs of diastereotopic
atoms and groups in the aryl moiety, whereas 2 and 4
form two diastereomeric pairs of enantiomers. As a con-
sequence of these stereochemical properties, the NMR
spectra show only one signal set for 1 and 3 but two
H
R9´ CH3 H CH3
H
Scheme 1. Structures of the N-acylalanine esters 1–4 and the enantio-
pure auxiliary (+)-(R)-Rh*.
enantiopure
MTPA4]7
dirhodium
complex
Rhð2IIÞ[(R)-(+)-
(Rh*:MTPA-H = methoxytrifluoromethyl-
phenylacetic acid ꢀ MosherÕs acid; see Scheme 1) is
added to a CDCl3 solution of a chiral substrate and a
1H NMR spectrum of this sample is recorded. Over
the course of this project, it turned out that soft-base
functionalities8 are particularly suitable for forming
rather stable adducts with Rh*. Thus, the dirhodium
method can be regarded as complementary to the appli-
cation of chiral lanthanide shift reagents (CLSR),9
which is optimal for hard-base functionalities. On the
other hand, hard Lewis-bases can be subjected to Rh*
as well, although the corresponding adducts are thermo-
dynamically labile. However, even multifunctional sub-
strates of this type can provide satisfactory results, in
particular, since Rh* shows a remarkable selectivity in
adduct formation. This has been demonstrated in the
for
2
and
4
in ratios of 2A:2B = 72:28 and
1
4A:4B = 70:30 as determined from H signal intensities.
It should be noted that a preparative separation of the
diastereomers in the samples of 2 and 4 was not possible;
for details see Experimental. However, due to restricted
internal mobility, it is possible to assign prochiral atoms
Figure 1. Structure of (2R)-1 as determined by X-ray diffraction; right: view along the N–C-10 bond.

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E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2287
Table 1. 1H and 13C chemical shifts of 1–4 in CDCl3 with a drop of acetone-d6 (in parts per million; see Experimental);a stereochemical assignment of
the two diastereotopic H-5 protons in 1 and 2 was not performed
1
2A/2B
3
4A/4B
H-2
H-3
H-5a
H-5b
H-6
H-30
H-40
H-50
H-60
H-70
H-80
H-90
C-1
4.52 (q)
1.04 (d)
3.73 (d)
3.64 (d)
3.81 (s)
7.14 (d)
7.24 (t)
7.18 (d)
—
4.79/4.24 (q)
1.15/1.49 (d)
3.78 d/3.76 (d)
3.71 d/3.72 (d)
3.79/3.78 (s)
7.13/n.d. (s)
4.53 (q)
1.10 (d)
5.67 (s)
4.78/4.24 (q)
1.18/1.54 (d)
5.70 s/5.71 (s)
3.82 (s)
7.16 (d)
7.27 (t)
7.20 (d)
—
3.80/3.79 (s)
7.15/n.d. (s)
—
—
7.07/n.d. (d)
7.36/7.22 (d)
2.23/2.34 (s)
2.36/2.35 (s)
—
7.10/n.d. (d)
7.37/7.26 (d)
2.25/2.34 (s)
2.37/2.37 (s)
—
2.18 (s)
—
2.22 (s)
—
2.48 (s)
172.38 (s)
55.85 (s)
14.80 (s)
166.83 (s)
41.87 (s)
52.21 (s)
135.86 (s)
137.36 (s)
128.86 (s)
129.45 (s)
129.29 (s)
138.47 (s)
18.27 (s)
—
2.49 (s)
171.58 (s)
56.38 (s)
14.76 (s)
164.82 (s)
63.30 (s)
52.36 (s)
135.27 (s)
137.56 (s)
129.15 (s)
129.72 (s)
129.66 (s)
138.51 (s)
18.35 (s)
—
172.33/171.46 (s)
55.62/59.14 (s)
14.28/15.40 (s)
166.72/166.49 (s)
42.18/42.15 (s)
52.30/52.30 (s)
134.26/136.76 (s)
136.44/136.03 (s)
132.10/132.23 (s)
139.49/139.25 (s)
128.11/128.21 (s)
129.66/128.95 (s)
17.76/17.96 (s)
20.98/20.95 (s)
—
171.59/170.74 (s)
56.07/59.80 (s)
14.18/15.19 (s)
164.56/164.18 (s)
63.60/63.71 (s)
52.45/n.d. (s)
133.51/136.23 (s)
136.47/135.93 (s)
132.32/132.43 (s)
140.06/139.81 (s)
128.29/128.43 (s)
129.60/128.88 (s)
17.88/18.05 (s)
21.05/21.01 (s)
—
C-2
C-3
C-4
C-5
C-6
C-10
C-20
C-30
C-40
C-50
C-60
C-70
C-80
C-90
18.54 (s)
18.68 (s)
a The 1H NMR data in the absence of acetone-d6 are the same within the experimental error limits; signal multiplicities: s, singlet; d doublet; t, triplet;
q, quartet.
C(=O)-CH2Cl
and groups in 1 and 3 as well as the respective diastereo-
mers in the mixtures of 2 and 4.
C(=O)-CH2Cl
C(=O)-CH2Cl
CH3OOC
CH3OOC
CH3OOC
H2
H2
H2
H
C
3CH3
C
C
Apart from the N–Ar moieties, there are two flexible
groups in the molecule: (a) the C(@O)–N bond and (b)
the carbon residue of the alanine [–CH(CH3)–
COOCH3]. The existence of only one single signal set
in 1 and 3 clearly proves that the amide adopts only
one single configuration, namely the E-configuration
as displayed in Scheme 1; the X-ray diffraction reveals
this configuration in the crystal, too (Fig. 1). In addi-
tion, an analogous configuration and conformation
has been published for a related phenylacetanilide
derivative.13
3
7·
7·
7·
9·
6·
6·
H
3
CH3
CH3
H3C
H3C
H3C
CH3
1
2A
[(2R),(aS)]
2B
[(2R),(aR)]
8·
CH3
8·
CH3
Figure 2. Preferred conformations of 1 and 2; the double arrows in
formular 1 (left) indicate NOE contacts; only the major enantiomers
with the (2R)-configuration are depicted.
the HMQC and HMBC evidence—a stereochemical
assignment for the pairs of diastereotopic methyl and
aromatic CH protons and carbons of 1 (see Table 1):
pro-(aS) for H-70/C-70 and pro-(aR) for H-90/C-90;
assignments for the atom pairs H-30/H-50, C-20/C-60
and C-30/C-50 are analogous. Dichloro derivative 3
shows spectra, which are very similar to those of 1 ex-
cept for H-5, C-5 and the amide carbon C-4 (Table 1).
Therefore, we assume that its stereochemical features
correspond to those of 1.
The –CH(CH3)–COOCH3 group can rotate about the
C-2–N bond at room temperature although some of
the respective conformations are energetically disfa-
voured, especially those with the bulky ester residues
directed towards the xylyl ring. The conformation in
the solid state (Fig. 1) is in excellent accordance with
our results extracted from the 2D NOESY spectrum of
1: there is a strong NOE contact between the methine
proton H-2 and only one of the methyl protons at the
phenyl group, namely H-70 (Fig. 2, left), whereas the
methyl H-3 signal shows NOE responses with both H-
70 and H-90. Under the assumption that the ester group
is stretched outwards (Figs. 1 and 2, left), the NOEs are
compatible with a conformation (Fig. 2, left) where the
torsion angle H-2–C-2–N–C-10 is around 100 20ꢂ.
Simultaneously, this provides—in combination with
As noted above, 2 and 4 form diastereomers due to the
asymmetric substitution of the xylyl group (20,40-di-
methylphenyl). Again, both compounds show spectra
totally analogous to each other (Table 1) except for H-
5, C-5 and C-4. Hence, the following configurational
assignment is described only for 2 but holds true for

´ ´
E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2288
both 2 and 4. It is based on a conformational analysis by
inspecting NOE contacts (here: selective 1D NOESY
experiments, Fig. 3).
ric repulsion, whereas there is no similar congestion in
2A whose methyl groups are further apart (Fig. 2).
2.2. Ligand—Rh* complexation modes—effect of acetone
Ligand molecules L can form 1:1- and/or 2:1-adducts
with the enantiopure dirhodium complex Rhð2IIÞ[(R)-
(+)-MTPA4]7 (Rh*) depending on the relative molar
ratio of L versus Rh*.8,10 All adducts—except those of
phosphane ligands—are kinetically labile so that
room-temperature NMR signals are averaged. NMR
signals may be shifted to some extent as compared to
those of the free ligands. In general, such complexation
shifts Dd are small or even negligible. Only if the com-
plexation site is close-by can noticeable deshielding
Dd-values be observed because the inductive effect of
the ligandÕs functional group is enhanced. Thus, com-
plexation shifts are good indicators for the preferred
complexation site if the donor is strong enough.
We started our investigation on the chirality recognition
of 1–4 under standard Ôdirhodium methodÕ conditions,
that is, one drop of acetone-d6 (ca. 4 ll; ca. 0.053 mmol
corresponding to 1–1.5 mol equiv relative to Rh*) was
added in order to enhance the solubility of Rh*.14 There-
by, a concentration can be achieved, which allows an
easy NMR measurement of 13C and other low-sensitiv-
ity-nuclei with a reasonable amount of spectrometer
time. If the functional groups used for adduct formation
are strong donors, such a small quantity of acetone-d6—
being a weak donor by itself—cannot compete and has
practically no effect on the complexation shifts and dis-
persions in molecules with such atoms or groups. How-
ever, if the donor ability of the ligands is comparable to
that of acetone-d6, one has to expect that acetone-d6
may ÔdiluteÕ, or in the worst case even annihilate chirality
recognition effects.
Figure 3. Trace (a): sections of the 500 MHz 1D 1H NMR spectrum of
2; trace (b): 1D NOESY with irradiation at H-2 of 2B, trace (c): 1D
NOESY with irradiation at H-2 of 2A.
Sample 2 consists of a major diastereomer 2A (72%) and
a minor one 2B (28%). This was deliberately prepared as
a non-racemic mixture [(2R):(2S) = 2:1] from enantio-
merically pure material with an already known absolute
configuration at C-2 (see below). For each diastereomer
2A (Fig. 2, centre) and 2B (Fig. 2, right), we found a pre-
ferred conformation (compare discussion of 1 above).
Irradiation on the signal of H-2 (Fig. 3c; d = 4.79),
belonging to the major diastereomer 2A, produces a
strong NOE contact with H-70 (short distance) whereas
the distance of H-2 to the aromatic proton H-60 is large
(weak NOE response). This is in accordance with the
conformation depicted in Figure 2 (centre). However,
when the signal of H-2 of 2B is irradiated (Fig. 3b;
d = 4.24), the sequence of NOE intensities is reversed
(Fig. 3c; strong for H-60 but weak for H-70) fitting to
the geometry of structure 2B in Figure 2 (right). It
should be noted that all other NOE effects observed in
further 1D NOESY spectra of 2 (not depicted) are in
agreement with this assignment.
This latter situation occurs, indeed, in the case of 1–4, as
can be seen from Table 2. Only a few 1H (H-3 and H-5)
and 13C (C-1 and C-4, the two carbonyl carbons) of the
monochloro compounds 1 and 2 showed significant
complexation shifts in the standard dirhodium method
experiment (with acetone-d6), while there was not even
a single atom in the dichloro derivatives 3 and 4 with
a significant Dd-value. If, however, acetone-d6 is ex-
1
cluded, the H complexation shifts of 1 and 2 increase
considerably (Table 2). Corresponding Dd(1H)-values
of 3 and 4 are still negligible without acetone-d6, but
the existence of significant dispersion effects (Table 3)
proves adduct formation. 13C complexation shifts in
the absence of acetone-d6 were recorded only for one
representative, ligand 2, due to the low solubility of
Rh* and the long spectrometer time, and here again
clear enhancements were observed, particularly for the
carbonyl atoms C-1 and C-4 (Table 2).
Thus, we have correlated the two chirality elements in
each stereoisomer. The major enantiomer of the major
diastereomer 2A is (2R,aS), while the minor enantiomer
of 2A is (2S,aR)-configured. Conversely, the major
enantiomer of the minor diastereomer 2B is (2R,aR)-
and the minor enantiomer of 2B is (2S,aS)-configured.
Simultaneously, this conformational and configura-
tional assignment provided an explanation as to why
2A is the major diastereomer and 2B the minor one.
The ratio of these diastereomers (ca. 70:30) indicates a
ground state energy difference DG0 ꢁ 2–2.5 kJ/mol.
There is always a rather close proximity of two methyl
groups 3 and 7 in the conformation of 2B causing a ste-
These observations lead to the following conclusions:
(a) Acetone-d6 is a serious competitor in the adduct
formation for hard ligands, such as the protected
amino acid ligands 1–4. This was shown from a
temperature-dependent 13C NMR experiment with

´ ´
E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2289
Table 2. Complexation shifts Dd of selected 1H and 13C NMR
resonances in 1–2;a in parts per million
(c) Adduct formation equilibria involving weak donor
ligands always contain a substantial proportion of
free ligand molecules, that is, the complexation con-
stants are low (presumably K < 1).8,15,16 This can
easily be monitored by the 1H chemical shift of
the MTPA methoxy group (d ca. 3.17 ppm) in the
experiments described,15 which is a typical value
for weak ligands with a low donor ability, that is,
for hard-base functionalities. Recently, we found
corresponding results for iodine atoms15 and phos-
phoryl groups (P = O).16 This is in sharp contrast to
soft-base functionalities, which give rise to equilib-
ria strongly biased in favour of the adducts
(MTPA–OCH3: d < 3.0).8,16d
1
2A/2B
Without
Acetone-d6
With
Without
With
Acetone-d6
H-2
H-3
H-5a
H-5b
H-6
C-2
+0.04
+0.06
+0.25
+0.32
+0.33
+0.05/0.07
+0.02/+0.07
+0.12/n.d.b
+0.09/n.d.
À0.04/À0.04
+0.5/+0.9
+1.6/n.d.
+0.14/+0.04
+0.12/+0.26
+0.36/+0.52
+0.26/+0.19
À0.10
+0.08
+0.12
+0.14
À0.06
+0.9
À0.11
c
+1.3/+2.3
+4.5 to +5
À1.8/À2.3
À0.3/À1.6
C-4
+2.2
C-5
À0.7/À1.0
À0.7/n.d.
C-20
C-40
(d) This conclusion is confirmed by temperature-
dependent 13C NMR experiments: only the C-1
(ester carbonyl), the C-4 (amide carbonyl) and the
C-5 (CH2Cl) signals approach coalescence on low-
ering the temperature of the NMR sample of 1
À0.1/À2.0
All samples contained an equimolar amount of Rh*. Values are
averaged if different for the enantiomers due to dispersion (see text).
Data are listed only for atoms with at least one Dd(1H)-value of ca.
0.1 ppm and larger or a Dd(13C)-value of ca. 1 ppm and larger. Sam-
ples were non-racemic mixtures with an enantiomeric ratio of (2R)/
(2S) = 3:2 for 1 and 2:1 for 2 (see text).
1
down to 203 K (1:Rh* = 1:1); all other 13C and H
signals did not show any significant line broaden-
ing. This coalescence indicates an equilibrium
between free ligands and ligands in the
adducts.8,15,16 Therefore, those minute coalescence
effects along with the low complexation shifts are
clear proof that a weak complexation exists.
a Complexation shifts Dd of 3 and 4 are negligible irregardless of the
presence or absence of acetone-d6.
b Ôn.d.Õ means: not detectable safely.
c Not recorded due to low concentration.
1, which will be discussed below (subsection d),
showing a coalescing carbonyl signal of acetone-d6.
(b) The complexation site in 1 and 2 is primarily the
amide carbonyl group (C-4). The Dd-values of the
ester carbonyl carbons (C-1) are much smaller; that
is, this carbonyl group is not the major binding site
although some minor contribution in the adduct
formation equilibria cannot be ignored. The intro-
duction of the second chlorine atom, however, pro-
hibits any effective adduct formation at the amide
group so that only the ester carbonyl is available
for ligation. This reveals a remarkable selectivity
in the adduct formation of multifunctional ligands
(see Section 2.3).
As a consequence, it is advisable to refrain completely
from adding acetone-d6 if the ligand investigated is a
weak donor (hard base). This, however, may result in
rather low sample concentrations (for details see Exper-
imental) and recording a 1H NMR spectrum with a
good signal-to-noise ratio may last for one or even more
hours. Moreover, 13C NMR spectroscopy may even be
impossible under such conditions.
2.3. Chirality recognition
Some signals of the chiral ligands 1–4 are split into two
due to the formation of diastereomeric adducts (chirality
Table 3. Dispersion effects Dm[= m(2R) À m(2S)] of the 1H NMR resonances in 1–4 in Hertz, recorded at 400 MHz in the presence an equimolar
amount of Rh*, with and without acetone-d6
1
2A/2B
3
4A/4B
Without
Acetone-d6
With
Without
Acetone-d6
With
Without
Acetone-d6
With
Without
Acetone-d6
With
H-2
H-3
À4.4
À0.6
0
À2.4
À3.5/À4.6
+4.0/À1.7
+9.2/n.d.a
+5.9/n.d.
+5.9/+5.9
n.d.
À2.9/À10.7
0
0
0
À2.3
0/À1.7
À2.2/À5.6
À5.7
+7.0
À7.0
+12.2
—
+6.2/À8.9
À4.1/+20.9
+6.0/+17.1
+11.7/+10.0
—
0
0
0
+2.0/À2.6
À1.4/À0.8
H-5a
H-5b
H-6
À1.0
À6.8
+6.9
n.d.
n.d.
n.d.
—
0
+0.7
—
0
0/À1.6
—
—
H-30
H-40
H-50
H-60
H-70
H-80
H-90
0
0
—
—
n.d.
—
0
0
—
—
0
0
0
0
—
—
—
+25.0
—
À6.5/n.d.
+6.3/À8.4
0/n.d.
À24.1/+12.8
+5.1/À44.4
—
—
0
—
—
0
+10.3
—
À4.0
—
À2.4/n.d.
0/0
—
—
0
0
—
À9.6
À22.8
—
—
0
All samples were non-racemic mixtures with an enantiomeric ratio of (2R)/(2S) = 3:2 for 1 and 2:1 for 2–4.
a Ôn.d.Õ means: not detectable safely.

´ ´
E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2290
recognition). The difference (in Hertz) between the indi-
vidual lines in such duplicated signals is the diastereo-
meric dispersion Dm (in Hertz), while their relative
intensities reflect the enantiomeric composition of the
ligand. Herein, mixtures with ratios (2R)/(2S) = 3:2 for
1 and 2:1 for 2–4 were prepared for the experiments
described (see Experimental). This allowed us to attri-
bute sets of NMR signals to the respective enantiomers.
the non-racemic mixtures can be identified easily from
their relative intensities. All Dm-values obtained are
shown in Tables 3 and 4.
There is no general pattern of smaller or larger Dm-val-
ues with respect to the position of the nuclei involved;
protons of ortho-methyl groups attached to the phenyl
(H-70, H-90) seem to be particularly sensitive.
In the standard dirhodium method experiment (with
acetone-d6),8,15,16 noticeable dispersion effects Dm
The potential of the dirhodium method for chirality rec-
ognition in this compound family is exemplified in Fig-
ure 4 for the H-6 (left) and the C-5 signals (right) of 2.
Moreover, the beneficial effect of recording H NMR
spectra in the absence of acetone-d6 is demonstrated in
Figure 5.
1
[= m(2R) À m(2S)] could be found for H and 13C NMR
1
signals of 1 and 2; they range up to ca. 25 Hz for both
sorts of nuclei. Signs can be attributed to these values
because the signals belonging to each enantiomer in
Table 4. Dispersion effects Dm[= m(2R) À m(2S)] of the observable 13C NMR resonances in 1–4, in Hertz, recorded at 100.6 MHz in the presence of an
equimolar amount of Rh*, with acetone-d6
1
2Aa
2B
3
4A
4B
C-1
C-2
C-3
C-4
C-5
C-6
C-10
C-20
C-30
C-40
C-50
C-60
C-70
C-80
C-90
À1.3
À3.1
+1.7
À4.2
+2.9
À1.0
À4.2
+2.7
+1.2
+3.1
0
(À10.7)
(+3.3)
(À1.9)
À2.5
(À6.7)
(+4.6)
(À3.8)
(n.d.)b
(+0.8)
(+1.5)
(+0.8)
(+10.5)
(n.d.)
(n.d.)
(n.d.)
(n.d.)
(+2.1)
(n.d.)
—
+1.5
0
À1.7
À1.3
+3.8
À1.5
0
0
0
0
0
À25.5
+10.2
À1.0
+0.8
+1.2
+1.3
0
(4.5–5)a
0À1a
0
0
0
0
0
(+2.9)
(+2.5)
(+7.5)
(+14.4)
(+5.4)
(À1.0)
(À29.5)
(À3.8)
(+2.1)
(+2.3)
—
+2.3
+1.0
0
0
0
+1.9
+1.0
0
À1.7
0
À0.6
À0.8
0
0
0
+1.7
+24.0
+3.6
À2.1
+1.0
+3.1
—
0
0
0
+5.4
n.d.
À5.2
+1.3
0
0
0
0
0À1
0À1
+1.1
—
0
0
0
+1.0
0
0
0
+0.6
+1.0
—
+0.6
+1.0
—
—
0
+0.6
—
The values in parentheses (for 2A and 2B) have been determined in the absence of acetone-d6. All samples were non-racemic mixtures with an
enantiomeric ratio of (2R)/(2S) = 3:2 for 1 and 2:1 for 2–4.
a A sign of this Dm-value could not be determined safely due to the low signal-to-noise ratio.
b Ôn.d.Õ means: not detectable safely.
2A
+5.9
R
2A
R
2B
+5.9
R
+2.7
S
S
2B
R
+2.3
S
S
3.77 3.76 3.75 3.74 3.73
41.6
41.4
41.2
Figure 4. Signals of methoxy atoms H-6 (left) and the chlorinated C-5 (right) of 2A/2B, recorded at 400 MHz and 100.6 MHz, respectively, in the
presence of an equimolar amount of Rh* and one drop of acetone-d6. The letters ÔRÕ and ÔSÕ refer to the absolute configurations at C-2. The numbers
on top of the signals are dispersions Dm (in Hertz). See text for the stereochemical assignment of the diastereomers 2A and 2B.

´ ´
E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2291
atom. This may be interpreted as a reflection of a signif-
icant selectivity of the Rh* auxiliary.
-9.6
+10.3
presence
of acetone-d6
4. Experimental
4.1. General
2.50
2.45
2.40
2.35
2.30
2.25
2.20
2.15
The syntheses of Rh*,7 14,17 and 34 have been described
before. All compounds 1–4 were synthesized starting
from either (R)- or (S)-methyl lactate (chiral pool).
For example, (S)-methyl lactate was mesylated and then
treated—after isolation—with the appropriate aniline to
give the (2R)-alanine derivative. Once isolated, it was
treated with the respective acyl chloride using anhydrous
K2CO3 as acid scavenger and THF as solvent. All prod-
ucts were isolated and purified by means of silica gel col-
umn chromatography using toluene–ethyl acetate (5:1)
as elution solvent. The identification of the products
-22.8
+25.0
absence
of acetone-d6
2.50
2.45
2.40
2.35
(ppm)
2.30
2.25
2.20
2.15
Figure 5. Signals of H-90 (left) and H-70 (right) of 1, recorded at
400 MHz with an equimolar amount of Rh* in the presence (top) and
absence (bottom) of acetone-d6. The numbers on top of the signals are
dispersions Dm (in Hertz).
1
was performed via H NMR and GC–MS. The purities
of the compounds were obtained by GC analysis using a
HP-1 column.
Enantiomeric purities were checked using a chiral
HPLC Nucleosil Chiral 3 column with 95% hexane (with
0.05% trifluoroacetic acid) and 5% isopropanol as sol-
vent system. The above mentioned procedure, starting
from the (R)-isomer of the methyl lactate, yielded the
corresponding (S)-metalaxyl isomers and analogues.
By analogy to the complexation shifts, the signal disper-
sions of the dichloroamides 3 and 4 differ from those of
the monochloro analogues in that they are much less sig-
nificant although there are still signals available for chi-
rality recognition (Tables 3 and 4). This proves again
that the dichloroamides donors are even weaker than
the monochloro analogues. The reason for this diver-
gent behaviour is unclear. The dipole character of the
amide carbonyl group itself should not be changed sig-
nificantly by the introduction of a second chlorine at
the a-position. Hence, steric repulsion between the
CHCl2 group and the approaching Rh* may be respon-
sible. Anyway, such a subtle sensitivity difference of the
donor ability of the two carbonyl groups is surprising
and reflects a remarkable selectivity of the soft
acid Rh* auxiliary towards multifunctional hard-base
ligands. This is reminiscent of the behaviour of xanth-
ines in analogous experiments.10 Rh* seems to be supe-
rior in this respect to the classical chiral lanthanide
shift reagents (CLSR),9 which—as hard acids—are not
as selective. Currently, we are further investigating this
phenomenon.
Compounds 2 and 4 formed diastereomeric mixtures,
which could not be resolved by HPLC methods. In
order to get information about the interconversion rate
(rotation about the chirality axis), we performed high-
1
temperature H and 13C NMR experiments with 2 dis-
1
solved in deuterated dibromoethane. Some H and 13C
signals showed line broadening on raising the tempera-
ture up to 400 K; in particular, the 13C signals of C-5
and C-60 show coalescence at 380–390 K. This results
in a barrier of ca. 70 kJ/mol proving that the life-times
of the individual diastereomers are shorter than 1 s at
room temperature and, thereby, too short for prepara-
tive separation.
4.2. Preparation of N-(chloroacetyl)-N-(2,6-dimethylphen-
yl)alanine methyl ester 1
Yield: 77% (S), 68% (R); mp 80 ꢂC. IR (ATR) cmÀ1
:
3. Conclusion
~m ¼ 2951, 1745 (C@O ester), 1672 (C@O amide), 1449,
1373, 1352, 1249, 1197, 1175, 1124, 779. LS-ESI-MS:
m/z = 286.1/284.1 (25/73) [M+H]+, 254.1/252.1 (28/78)
[MÀOCH3]+, 226.1/224.1 (37/100) [MÀCOOCH3]+,
148.1 (10) [MÀCOOCH3ÀCOCH2Cl+H]+; HR-ESI-
MS: 284.1066, calculated for C14H1835ClNO3 284.1053.
The compounds 1–4 provide interesting stereochemical
features allowing an assignment of absolute configura-
tions in mixtures of diastereomers 2 and 4, with respect
to their NMR properties and ground state enthalpies.
We found that donors, even as weak as an amide or
ester groups, can still be effective enough for chirality
recognition although the formation of adducts with
Rh* may be so weak that practically no complexation
shifts can be observed. The presence or absence of ace-
tone-d6, used for enhancing the solubility of Rh*, may
play a decisive role for such ligands. A clear competition
between the two carbonyl groups was observed, which
can be manipulated by introducing a second chlorine
20
D
20
D
(R): ½aŠ ¼ À45.9 Æ 1 (c 0.038, CHCl3), (S): ½aŠ
¼
þ45.1 Æ 1 (c 0.05, CHCl3).
4.3. Preparation of N-(chloroacetyl)-N-(2,4-dimethylphen-
yl)alanine methyl ester (2); mixture of diastereomers
Yield: 76% (S), 68% (R); viscous oil. IR (ATR) cmÀ1
~m ¼ 2950, 1743 (C@O ester), 1668 (C@O amide), 1500,
1376, 1233, 1202, 1104, 787, 737. LS-ESI-MS:
:

´ ´
E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2292
m/z = 286.1/284.1 (28/81) [M+H]+, 254.1/252.1 (24/72)
[MÀOCH3]+, 226.1/224.1 (37/100) [MÀCOOCH3]+,
148.1 (14) [MÀCOOCH3ÀCOCH2Cl+H]+; HR-ESI-
MS: 284.1043, calculated for C14H1835ClNO3 284.1053.
Table 5. Crystallographic parameters of 1
Diffractometer
IPDS, Fa. Stoe, Darmstadt,
Germany
300(2) K
Mo Ka, 0.71073 A
Temperature
Irradiation
˚
h
Index range
min, hmax
2.20ꢂ, 24.27ꢂ
4.4. Preparation of N-(dichloroacetyl)-N-(2,6-dimethyl-
phenyl)alanine methyl ester 3
À9 6 h 6 +9; À20 6 k 6 +20;
À21 6 l 6 +21
Reflections collected unique
R indices
15,889/4167 [Rint = 0.1346]
R1 = 0.0845, wR2 = 0.1566
C14H18ClNO3
Yield: 80% (S), 76% (R); mp 137–139 ꢂC. IR (ATR)
cmÀ1: m ¼ 2960, 1750 (C@O ester), 1676 (C@O amide),
~
Empirical formula
Formula weight
Crystal system
1376, 1350, 1268, 1195, 788, 723, 700, 666. LS-ESI-
MS: m/z = 322.1/320.1/318.2 (9/53/82) [M+H]+, 290.0/
288.0/286.0 (10/56/90) [MÀOCH3]+, 262.0/260.0/258.0
283.74
Orthorhombic
P21 21 21 (no. 19)
Space group
Unit cell dimensions
(12/64/100)
[MÀCOOCH3]+,
222.1/224.1
(4/1)
˚
a = 8.919(1) A
[MÀCOOCH3ÀHCl]+, 148.1 (3) [MÀCOOCH3À
˚
b = 17.957(2) A
˚
COCH2Cl+H]+; HR-ESI-MS: 318.0674, calculated for
c = 18.509(3) A
3
˚
20
D
C14H1735Cl2NO3 318.0664. (R): ½aŠ ¼ À20.4 Æ 1 (c
Volume
Z
2964.4(7) A
20
0.051, CHCl3), (S): ½aŠ ¼ þ19.7 Æ 1 (c 0.05, CHCl3).
8
1.272 g/cm3
D
Calculated density Dx
Absorption coefficient l (Mo Ka) 0.261 mmÀ1
Crystal size
Absolute structure parameter
Largest diff. peak and hole
4.5. Preparation of N-(dichloroacetyl)-N-(2,4-dimethyl-
phenyl)alanine methyl ester 4; mixture of diastereomers
0.7 · 0.35 · 0.26 mm
0.0(2)
0.302 and À0.276 e A
À3
˚
Yield: 79% (S), 69% (R); viscous oil. IR (ATR) cmÀ1
:
~
m ¼ 2951, 1746 (C@O ester), 1685 (C@O amide), 1499,
1453, 1378, 1325, 1204, 1103, 806, 671. LS-ESI-MS: m/
z = 322.1/320.1/318.2 (11/54/82) [M+H]+, 290.0/288.0/
286.0 (9/51/81) [MÀOCH3]+, 262.0/260.0/258.0 (12/65/
100) [MÀCOOCH3]+, 222.1/224.1 (3/4) [MÀCOOCH3À
HCl]+, 148.1 (2) [MÀCOOCH3ÀCOCH2Cl+H]+; HR-
ESI-MS: 318.0674, calculated for C14H1735Cl2NO3
318.0664.
intensities. In the standard dirhodium experiment, one
drop of acetone-d6 was added to each NMR sample
before measurement in order to increase the solubility
of Rh*.14 Thereby, 48.6 mg (42 lmol) of Rh*, an equi-
molar amount of the ligands 1–4 and ca. 4 ll acetone-
d6 (ca. 53 lmol corresponding to 1–1.5 mol equiv
relative to Rh*) were dissolved in 0.7 ml CDCl3. In the
absence of acetone-d6, however, only 16.2 mg of Rh*
(ca. 14 lmolar) could be dissolved in 0.7 ml CDCl3.
4.6. NMR spectroscopy
Most room-temperature 1H (400.1 MHz) and 13C
(100.6 MHz) were performed on a Bruker Avance
DPX-400 spectrometer. Some spectra were recorded at
500.1 MHz (1H) and 125.6 MHz (13C) on a Bruker
Avance DRX-500 spectrometer. Chemical shift stan-
dards were internal tetramethylsilane (d = 0) for 1H
and 13C. Signal assignments were assisted by DEPT,
COSY, HMQC, HMBC, NOESY and ROESY (stan-
dard Bruker software).
4.7. X-ray structure determination of 1
For data see Table 5. There are two molecules in the
asymmetric unit, which differ mainly in the N–C-4–C-
5–Cl torsion angle: 169ꢂ and À145ꢂ. Atomic distances,
bond angles and torsion angles can be requested from
the corresponding author as supplementary material.
CCDC 261197 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retriev-
ing.html or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK,
fax (+44) 1223 336 033, e-mail deposit@ccdc.cam.ac.uk.
An X-ray diffraction study of a related structure—Cl
in 1 is replaced by C6H5—has been published by Bart
et al.13
1D and 2D NOESY as well as ROESY experiments
were recorded at 500 MHz using standard Bruker
microprograms. Mixing times were 300 ms in the selec-
tive 1D und 2D NOESY and 250 ms in the 2D ROESY
experiments. There was no significant difference in the
spectral information of NOESY as compared to
ROESY applications.
Variable-temperature 1H (500.1 MHz) and 13C NMR
(125.6 MHz) spectra were recorded in the presence of
Rh* on a Bruker Avance DRX-500 spectrometer. Tem-
peratures were read from the instrument panel; no fur-
ther measures for more precise temperature
determinations were taken.
Acknowledgements
This work has been performed within the project ÔBio-
logically Active Natural Products: Synthetic DiversityÕ
(Department of Chemistry, Hannover University) and
was supported by the Deutsche Forschungsgemeinschaft
(Projects 436 UNG 113/148), by the Hungarian Acad-
emy of Sciences (Project NMTA/DFG 2002-2004) and
the Hungarian National Research Foundation (OTKA
Mixtures with molar ratios of (2R)/(2S) = 3:2 for 1 and
2:1 for 2–4 were prepared for the NMR experiments in
the presence of Rh* so that the enantiomers could be
discerned easily from each other by their relative signal
´ ´
T046127). A.S. thanks for Bekesy and Varga/Rohr fel-

´ ´
E. Dıaz Gomez et al. / Tetrahedron: Asymmetry 16(2005) 2285–2293
2293
5. Swiech, T.; Bakuniak, E.; Zielinski, W. Pestycydy (War-
saw) 1992, 27–32; Chem. Abstr. 119, 264571.
6. Gozzo, F.; Barino, L.; Scordamaglia, R. Tagungsbe-
richt—Akademie der Landwirtschaftswissenschaften der
Deutschen Demokratischen Republik, 1987; Vol. 253, pp
77–83; Chem. Abstr. 109, 18763.
lowships. The authors wish to thank Mr. Juan Carlos
Iglesias Perez from IPESA S.A. for permitting us to dis-
close this information about the substances studied. J.J.
thanks the German Academic Exchange Service
(DAAD) for a fellowship at Hannover University.
C.O.D.V., a member of the Carrera del Investigador
of CONICET, also thanks the Volkswagen Foundation
for generous support of part of this work and the
ANPCYT–DAAD for the German–Argentinian Coop-
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ANPCYT and to the Consejo Nacional de Investigaci-
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