Asymmetric synthesis of 2-methyl cyclohexane carboxylic acids by heterogeneous catalysis: Mechanistic aspects

Article abstract of DOI:10.1002/(SICI)1521-3765(20000317)6:6<949::AID-CHEM949>3.0.CO;2-H

The catalytic hydrogenation of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates was studied over supported rhodium and ruthenium catalysts at room temperature and a pressure of 5 MPa. The reaction was diastereoselective with the predominant formation of (1S,2R)-2-methylcyclohexane carboxylic acid with a diastereomeric excess (de) of up to 96%. The most stable conformation was determined by means of a combination of modelling calculations, NMR spectroscopy and X-ray structural determination. In this conformation, the carbonyl group of the pyroglutamate auxiliary shields one face of the aromatic ring. The observed selectivity may thus be explained by a preferential adsorption at the unshielded face which avoids steric repulsion by the C=O group to result in a cis hydrogenation. The addition of an amine, the nature of the support (alumina or active carbon) or of the metal (Rh or Ru) were shown to give additional stabilisation of the adsorption at the unshielded face to increase the diastereoisomeric excess.

Full text of DOI:10.1002/(SICI)1521-3765(20000317)6:6<949::AID-CHEM949>3.0.CO;2-H

FULL PAPER
Asymmetric Synthesis of 2-Methyl Cyclohexane Carboxylic Acids by
Heterogeneous Catalysis: Mechanistic Aspects
MicheÁle Besson,* Françoise Delbecq, Pierre Gallezot, Samuel Neto, and Catherine Pinel[a]
Abstract: The catalytic hydrogenation
of (S)-alkyl-N-(2-methylbenzoyl)pyro-
glutamates was studied over supported
rhodium and ruthenium catalysts at
room temperature and a pressure of
5 MPa. The reaction was diastereoselec-
tive with the predominant formation of
(1S,2R)-2-methylcyclohexane carboxylic
acid with a diastereomeric excess (de) of
up to 96%. The most stable conforma-
tion was determined by means of a
combination of modelling calculations,
NMR spectroscopy and X-ray structural
determination. In this conformation, the
carbonyl group of the pyroglutamate
auxiliary shields one face of the aromat-
ic ring. The observed selectivity may
thus be explained by a preferential
adsorption at the unshielded face which
ˆ
avoids steric repulsion by the C O
group to result in a cis hydrogenation.
The addition of an amine, the nature of
the support (alumina or active carbon)
or of the metal (Rh or Ru) were shown
to give additional stabilisation of the
adsorption at the unshielded face to
increase the diastereoisomeric excess.
Keywords: aromatic rings ´ diaster-
eoselectivity ´ heterogeneous catal-
ysis
´
hydrogenations
´
steric
hindrance
other functionalities, is the lack of understanding of the nature
and strength of this interaction. Covalent bonding should
provide the strongest interaction and the asymmetric induc-
tion can then be accomplished with the help of a chiral
auxiliary temporarily grafted to the substrate, thus sterically
blocking the reaction at one face of the substrate.[8±11] We have
already reported the catalytic hydrogenation of unsymmetri-
cally substituted aromatics, such as o-toluic acid, by means of
chiral auxiliaries, such as proline alkyl esters.[12] The asym-
metric reaction of (S)-methyl-N-(2-methylbenzoyl)proline
ester with supported Rh and Ru catalysts yielded the
corresponding cis cyclohexyl hydrogenated products with
de ꢀ 68%. The de and configuration were found to be
remarkably dependent on the nature of the metal, the support
and on the presence of the bulky achiral amine (ethyl-
dicyclohexylamine ˆ EDCA).[12] Ranade et al. reported the
diastereoselective hydrogenation of anthranilic acid[13, 14] and
of o-toluidine covalently bonded to (S)-proline. Diastereose-
lectivities of up to 96% were reported for the former,
probably as a consequence of the rigidity of the substrate;
however, the yield was moderate on account of the large
amount of the trans compounds. The best de for the hydro-
genation of the aromatic amine was 57%. The diastereose-
lectivity was also shown to be dependent on the nature of the
metal (Rh or Ru), the support and the process conditions.
Simultaneously, Tungler et al.[15] and Besson et al.[16] described
the diastereoselective hydrogenation of pyridine derivatives
with proline as the chiral auxiliary ligand over metallic
supported catalysts.
Introduction
Chiral cyclohexyl derivatives are present in a large number of
natural products of biological importance.[1, 2] They can also be
used as chiral auxiliaries.[3] Thus, the development of methods
for the asymmetric synthesis of these compounds generates
considerable interest. The conventional synthesis of optically
active cyclohexyl molecules is painstaking and costly; it
involves an asymmetric Diels ± Alder reaction between buta-
diene and N- or O-propenoyl derivatives,[4] or the use of
enzymatic resolution.[5] An attractive method for the prepa-
ration of these compounds would be the hydrogenation of
substituted aromatic compounds by heterogeneous catalysis
in an enantioselective or diastereoselective approach. In the
former, the metallic surface is modified with an adsorbed
chiral organic compound. However, there are, to date, only
two efficient catalytic systems: the tartaric acid-modified
nickel catalysts and the platinum ± cinchona alkaloid system.
Both of these systems are substrate specific and not directly
applicable to aromatic compounds.[6, 7] The interaction be-
tween the reactant and the chiral modifier is responsible for
the enantioselectivity. However, the major obstacle to the
expansion of the applicability of these catalysts, or in
developing new catalysts for the asymmetric conversion of
[a] Dr. M. Besson, Dr. F. Delbecq, Dr. P. Gallezot, Dr. S. Neto, Dr. C. Pinel
Institut de Recherches sur la Catalyse-CNRS
2, Avenue Albert Einstein, 69626 Villeurbanne Cedex (France)
Fax : (‡ 33)4-7244-5399
E-mail: mbesson@catalyse.univ-lyon1.fr, pinel@catalyse.univ-lyon1.fr
Chem. Eur. J. 2000, 6, No. 6
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M. Besson et al.
FULL PAPER
Other chiral auxiliaries with a structure close to proline
(prolinol, (S)-(2-pyrrolidinylmethyl)pyrrolidine, (R)-panto-
lactone) were screened for the hydrogenation of o-toluic
acid, but their diastereoselectivity was less than that of
proline.[17] We recently reported[18] that high selectivities
(ꢀ95%) could be achieved by the use of (S)-pyroglutamic
acid methyl ester as the chiral auxiliary. The present study was
designed to provide a better understanding of the origin of the
asymmetry in this reaction. In order to get a molecular picture
of the adsorption ± hydrogenation step and to obtain infor-
mation on the reaction mechanism, molecular modelling and
NMR analyses were performed along with an X-ray structure
determination of the molecule. Additionally, the influence of
the nature of the ester group (Et, iPr, tBu, n-octyl) has been
studied.
presence of the cyclohexenic intermediate 2 was also estab-
lished by comparison with a reference prepared by an
alternative route. Similar compounds have been also observed
for the hydrogenation of the (S)-methyl-N-(2-methylben-
zoyl)proline ester.[12] The remaining products could not be
identified unambiguously, but they were shown to have no
influence on the diastereoselectivity.
The selectivity of the cyclohexanoic compound for the
hydrogenation reaction is given by Equation (2). Typically, a
low selectivity reflects the formation of a large amount of
Results
Identification of the reaction products: The asymmetric
hydrogenation of the aromatic substrate 1, formed by covalent
bonding of o-toluic acid and alkyl pyroglutamate in ethanol at
room temperature and under 5 MPa hydrogen pressure, gave
four cyclohexane diastereoisomers: the cis isomers 3a and 3b
and the trans isomers 4a and 4b (Scheme 1).
ˆ
side-products. As a result of the conversion of the C C
intermediate, the selectivity increases slightly after total
conversion of the aromatic ring.
S ˆ [%(3a ‡ 3b ‡ 4a ‡ 4b)/%conversion1]  100
(2)
For the hydrogenation of the esters iPr, tBu and n-octyl, gas
chromatography (GC) was adequate for the separation of the
four isomers. The synthesis of (S)-octyl-N-(2-methyl cyclo-
hexane carbonyl)pyroglutamate allowed the assignment of
the cis and trans isomers by the measurement of the optical
rotation in ethanol of a sample that contained no trans-
hydrogenated products. A rotation ([a]D < 0) in the same
sense as that of (1S,2R)-2-methyl cyclohexane carboxylic acid
Hydrogenation of (S)-methyl-N-(2-methylbenzoyl)pyro-
glutamate over rhodium catalysts: Figure 1 gives the product
([a]2D5
ˆ
5.2, c ˆ 1 in EtOH)[19] was observed, which suggest-
ed that the major hydrogenated isomer was ( )-(1S,2R,2'S)-
methyl-N-(2-methylbenzoyl)pyroglutamate 3b.
In the case of the methyl and ethyl esters, the four alicyclic
isomers were not all separated by GC: only three peaks were
detected and were subsequently assigned.[20]
The de of the cis isomers was defined by Equation (1),
which uses the relative percentages of the chromatographic
areas of the two peaks assigned to 3a and 3b.
de ˆ [(%3a %3b)/(%3a ‡ %3b)]  100
(1)
In addition to the products described above, some other
peaks were detected during the course of the reaction. One
was attributed to the alkyl pyroglutamate 5, formed by
hydrolysis of the amide bond in the aromatic compound. The
Figure 1. Distribution of the products as a function of time for the
hydrogenation of 1 (R ˆ Me) over 3.6% Rh/C. Reaction conditions:
2.27 mmol 1, 0.105 mmol Rh, 130 mL ethanol, room temperature, 5 MPa
hydrogen.
Scheme 1. Diastereoselective hydrogenation of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates.
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Asymmetric Synthesis
949±958
distribution as a function of time for the hydrogenation of (S)-
methyl-N-(2-methylbenzoyl)pyroglutamate over a 3.6 wt%
Rh/C catalyst. The cyclohexane derivatives 3a and 3b, which
result from a cis hydrogenation of the aromatic ring, were
detected in high proportions. Throughout the reaction, the de
was 50% in favour of 3b and was constant with the conversion
of the aromatic substrate. The cyclohexenic compound 2 was
formed with a maximum yield of 27% and was consecutively
hydrogenated to 3a, so that the de decreased progressively to
35%. The percentage of trans diastereoisomers formed did
not exceed 5%.
While in the case of the methyl prolinate auxiliary, the
hydrogenation of the cyclohexenic compound was total,[12] in
the case of the pyroglutamate auxiliary, the reaction stopped
although 13% of compound 2 still remained. Allowing the
reaction to proceed for an additional period of 16 h did not
result in any further conversion. This may possibly be the
result of the steric hindrance of the tetrasubstituted double
bond, which would significantly inhibit the approach of 2
towards the metallic surface. Molecular modelling of this
intermediate is underway to confirm this hypothesis. In a
similar study of the hydrogenation of (S)-proline-modified
anthranilic acid on Rh and Ru catalysts, a lower rate of
hydrogenation of the cyclohexenic intermediate, relative to
the aromatic substrate, was also observed.[13] Methyl pyroglu-
tamate, formed by hydrogenolysis of the amide bond in the
aromatic compound, appeared from the beginning of the
reaction and attained its maximum (9% chromatographic
area) at 100% conversion of 1. Toluic acid, which is formed
during this hydrolysis process, may also poison the catalyst.
Because of the presence of many by-products, the selectivity
of the reaction in favour of the cyclohexanoic compound was
modest: from an initial 52% up to 65% after partial reduction
of 2 to 3a and 3b.
observed[12]), the initial reaction rate decreased (4.3 instead of
23.5 molh 1 molRh 1); this was caused by the partial covering
of the rhodium particles by the amine. The catalyst then
deactivated rapidly and the reaction ceased after 60%
conversion. However, with the addition of EDCA, the
diastereoselectivity was improved to 91% in favour of the
same configuration 3b. The de was also constant with
conversion of 1. The semi-hydrogenated compound 2 was
formed with a maximum yield of 3.5% compared with 27%
on the same catalyst without the amine EDCA. No trans
isomers were detected; this was confirmed by the hydrolysis
of the hydrogenated solution and the analysis of the 2-meth-
ylcyclohexane carboxylic acids obtained. The selectivity of the
reaction for the cyclohexane isomers was improved to 85%.
The amount of methyl pyroglutamate was only 3% (com-
pared with 9% in the absence of amine) and the other by-
products were negligible. The origin of the poisoning ob-
served in this reaction is not clear, but it may be caused by the
presence of EDCA, which may react with by-products and
yield poisoning compounds.
The distribution of products over 3.7 wt% Rh/Al2O3
catalyst is given in Figure 3. As previously observed in the
case of the methyl prolinate,[15] a great improvement in the
diastereoselectivity was obtained by the use of an alumina
A bulky amine (ethyldicyclohexylamine, EDCA), which
was found to have a beneficial effect on the diastereoselec-
tivity during the hydrogenation of (S)-methyl-N-(2-methyl-
benzoyl)proline ester,[12] was added to the reaction medium
(molar ratio EDCA/Rh ˆ 2). The product distribution ob-
tained is shown in Figure 2. As expected (and as previously
Figure 3. Distribution of products as a function of time for the hydro-
genation of
1
(R ˆ Me) over 3.7% Rh/Al2O3. Reaction conditions:
2.27 mmol 1, 0.108 mmol Rh, 130 mL ethanol, room temperature, 5 MPa
hydrogen.
support rather than activated carbon. Indeed, although the
1
reaction rate was seven times lower (3.3 molh 1 molRh
compared with 23.5 molh 1 molRh 1), the de was 90% in
favour of 3b. Trans isomers were not observed and the
cyclohexenic 2 compound was formed with a yield of 5%.
Only 6% methyl pyroglutamate at its maximum was detected
as a by-product. Thus, a very selective reaction was achieved
(>90% for the cyclohexane isomers). A decrease in the
reaction rate was observed after 50% conversion of 1. The
reason for this deactivation is unclear, but it is probably
caused by some modifications of the metallic surface (i.e.,
change of morphology or the oxidation state). Indeed, as
Figure 2. Distribution of products as a function of time for the hydro-
genation of 1 (R ˆ Me) over 3.6% Rh/C in the presence of EDCA.
Reaction conditions: 2.27 mmol 1, 0.105 mmol Rh, 0.22 mmol EDCA,
130 mL ethanol, room temperature, 5 MPa hydrogen.
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M. Besson et al.
FULL PAPER
reported earlier for XPS studies of the catalyst in the
hydrogenation of the prolinate derivative of o-toluic acid[12]
,
and as observed by Ranade et al[14] in EXAFS and XANES
studies, the rhodium catalyst loses its activity when it is
prereduced, or reduced during the course of the experiment.
The addition of the amine to 3.7 wt%Rh/Al2O3, in a molar
ratio EDCA/Rh ˆ 2, slightly decreased the initial reaction
rate (2 molh 1 molRh 1), but further improved the diastereo-
selectivity to ꢀ95% in favour of 3b. No trans product and
very low amounts of cyclohexenic compound 2 were formed.
Influence of the nature of the ester group over the rhodium
catalysts: To check whether the diastereoselectivity showed a
dependence on the nature of the substituent R in the
pyroglutamate ester, the hydrogenation of the substrate 1
(R ˆ Et, iPr, n-octyl and tBu) was investigated over the Rh/C
and Rh/Al2O3 catalysts, with and without EDCA. For both
rhodium catalysts, and with all the substituted esters, the
product distributions as a function of time were very similar to
those obtained with the methyl ester. Complete conversion of
1 could be obtained with Rh/C in the absence of the amine;
the conversion was 50 ± 80% in the other cases. An example is
given for the hydrogenation of N-(2-methylbenzoyl)-(S)-tert-
butyl pyroglutamate in the presence of Rh/C (Figure 4). The
data are summarised in Table 1.
Without EDCA (Figure 4a), the aromatic substrate 1 (R ˆ
tBu) was rapidly converted into the cis and trans alicyclic
compounds and the cyclohexenic compound 2. The latter
attained a maximum at 100% conversion of 1 and was
subsequently hydrogenated; however, as observed with the
methyl ester, the reaction stopped and the percentage of 2
remained constant, even after a period of 50 hours. In the
presence of EDCA (Figure 4b), the reaction was much slower
and although the substrate was not totally hydrogenated, the
de improved from 66 to 92%.
As regards the diastereoselectivity data, it can be seen from
Table 1 that the de on Rh/C without amine increased with the
bulkiness of the R group of the ester: Me (35%) < Et ꢁ iPrꢁ
n-octyl < tBu (60%). The maximum amount of semi-hydro-
genated 2 formed was almost the same (ꢁ25%) in all
experiments. The addition of EDCA to the reaction medium
in the presence of Rh/C improved the de (90 ± 92%).
Figure 4. Product distribution as a function of time for the hydrogenation
of 1 (R ˆ tBu) in the presence of Rh/C. Reaction conditions: 2.27 mmol 1,
0.105 mmol Rh, 130 mL ethanol, room temperature, 5 MPa hydrogen,
a) without amine, b) EDCA/Rh ˆ 1.5.
ester group. The best de found was 96% in favour of 3b, for
the hydrogenation of the octyl ester.
Influence of the formation of the by-products on the
selectivity: Although the by-products formed were not
considered in the measurement of the diastereoselectivity,
some tendencies may be noted as regards the selectivity in
alicyclic compounds and the amount of alkyl pyroglutamate
formed. The data obtained are collected in Table 2.
In the absence of the amine, significantly higher diaste-
reoselectivities (de ˆ 88 ± 90%) could be achieved on Rh/
Al2O3 as compared with the Rh/C catalyst (35 ± 60%). In the
presence of the amine (EDCA/Rh ˆ 1.5 ± 2), the de was
slightly improved and was not dependent on the size of the
Table 1. Data for the hydrogenation of 1 over 3.6% Rh/C and 3.7% Rh/Al2O3.
Rh/C
Rh/C ‡ EDCA
Rh/Al2O3
de [%] %2
Rh/Al2O3 ‡ EDCA
R in 1
de [%][a]
%2[a]
de [%]
%2
de [%]
%2
Me
Et
iPr
tBu
n-octyl
50 (max) ± 35
65 (max) ± 46
56 (max) ± 44
66 (max) ± 60
58 (max) ± 53
27 (max) ± 13
32 (max) ± 21
22 (max) ± 10
18 (max) ± 7
27 (max) ± 10
91
90
90
92
±
4
3
6
4
±
90
88
90
> 90
±
5
94
89
94
95
96
3.5
2.5
2.5
2.7
2.5
5
5
4
±
[a] From the beginning of the reaction, 1 was hydrogenated mainly to cis-3a and cis-3b with a de in favour of 3b which attained a maximum at 100%
conversion of 1. The intermediate 2 was then hydrogenated preferentially to 3a with, as a consequence, a decrease in the de. The values are given at maximum
and at the plateau.
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Asymmetric Synthesis
949±958
Table 2. Selectivity for the cyclohexanoic derivatives and amount of alkyl
pyroglutamate formed during hydrogenation of 1 (percentages of chroma-
tographic areas).
formed and de obtained with the different Ru catalysts tested
are given in Table 3.
The hydrogenation was quasi-quantitative in each case, but
lower reaction rates were obtained when catalysts on oxide
supports were used. After a rapid initial disappearance of
Table 3. Hydrogenation of 1 (R ˆ Me) on supported ruthenium catalysts.
Initial reaction
rate [molh 1 molRu
Max. yield de at max. 2[%]
]
2[%]
(conversion
of 1[%])
5% Ru/C
14.4
4.8
2.6
1.7
19
10
11
19
74 (99)
83 (61)
85 (61)
78 (70)
5% Ru/C ‡ EDCA
3.5% Ru/Al2O3
2.8% Ru/TiO2
substrate 1 up to 75% conversion, the reaction rate decreased.
The semi-hydrogenated compound 2 was reduced at a low
rate. High diastereoselectivities of 74%, 85% and 78% were
achieved with Ru/C, Ru/Al2O3 and Ru/TiO2 catalysts, respec-
tively, the major product being 3b. These de values were
obtained from the start of the reaction and remained constant
up to complete conversion. Only 3 ± 6% methyl pyrogluta-
mate was formed and no other by-products were detected.
The addition of EDCA to the Ru/C catalyst (EDCA/Ru ˆ
Alkyl pyroglutamate[%]
R
Rh/C[a]
Rh/C ‡ EDCA
3
3
7
15
±
Rh/Al2O3
Me
Et
iPr
tBu
n-octyl
9 ± 4
9 ± 5
10 ± 4
25 ± 10
13 ± 7
6
13
11
20
±
[a] Percentages at maximum (at almost complete conversion of 1) and at
the end of the reaction.
2.2) slowed down the reaction by
a factor of three
1
(4.8 molh 1 molRu compared to 14.4molh 1 molRu 1), but
The by-products detected were alkyl pyroglutamate esters
and a compound with a GC retention time very close to that of
the semi-hydrogenated compound 2 (i.e., in the case of the
methyl ester, compounds were detected at 14.53 and
14.83 min, compared with 14.63 min for compound 2). We
verified that none of these by-products corresponded to a
transesterification reaction with the ethanol solvent, but their
structures could not be elucidated. Owing to the formation of
these by-products and the formation of compound 2, which is
not totally hydrogenated, the selectivity for cyclohexanoic
derivatives was in the range 55 ± 90%.
In all experiments, alkyl pyroglutamate was formed by
hydrolysis, with a maximum percentage of 25% attained with
the tert-butyl ester over Rh/C. This compound was formed
continuously from the aromatic substrate until its complete
conversion. Subsequently, its concentration in the reaction
medium decreased in all experiments performed with Rh/C
without amine, while its concentration remained constant in
the other experiments (Table 2). The addition of an amine to
Rh/C or Rh/Al2O3 limited the extent of that hydrolysis.
Considering all the esters, the use of Rh/C yielded
numerous by-products. It is noteworthy that both the dis-
appearance of alkyl pyroglutamate and the formation of these
by-products occurred only over the Rh/C catalyst used
without amine. One might assume that these two phenomena
correspond to the occurrence of the same type of modification
of the auxiliary, whether it is bound to the surface or to the
aromatic ring or not. The carbon support might be responsible
for that transformation.
the diastereoselectivity improved slightly from 74% to 81%.
Discussion
Preferred conformation of substrate 1: In order to show the
influence of several factors described on the diastereoselec-
tivity, the structure of the aromatic substrate was determined
by different techniques, which included molecular modelling,
1H NMR spectroscopy and X-ray structure determination.
Molecular-modelling calculations were carried out in order
to predict the major conformations of 1 (R ˆ Me), by allowing
rotation about C2 C1, C1 N, C12 C13 and C13 O3 (Fig-
ure 5). As a result of these investigations, four stable
Figure 5. Numbering scheme for 1.
conformations were found. Figure 6 shows the ball-and-stick
drawings of these lowest-energy conformations as well as the
respective corresponding calculated energies.
The geometry of the four isomers is very similar to that
obtained by conformational analysis of the o-toluic acid/
prolinate substrate. The main difference between the con-
formers is the position of the pyroglutamate group with
Hydrogenation of methyl ester over ruthenium catalysts: The
initial reaction rate, maximum percentage of intermediate 2
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M. Besson et al.
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aromatic ring; namely the hydrogen atom on C3 (Figure 5 and
rotation angle ꢁ1808 in Figure 7) and the more bulky methyl
group on C7 (Figure 5 and rotation angle ꢁ3608 in Figure 7)
which prevent the free rotation about that bond.
Similarly, the energy barrier required for free rotation
about the C1 N bond was calculated (Figure 8). This calcu-
lation yielded high energy barriers, which are again indicative
Figure 6. Conformers of substrate 1 after geometry optimisation.
respect to the aromatic ring. In conformers A and B the chiral
auxiliary is situated above the aromatic ring, while in con-
formers C and D this moiety is situated below. The pairs of
conformers (A ‡ B and C ‡ D) vary by rotation of the
pyroglutamate about the C1 N bond; this results in the
auxiliary being directed over or pointed away from the
aromatic ring. The molecular-modelling calculations of the
prolinate derivative revealed the existence of four energeti-
cally equivalent isomers; this was also confirmed by 1H NMR
spectroscopy. So, in contrast to the calculation performed
previously for the prolinate auxiliary,[12] these four conformers
with the pyroglutamate auxiliary do not have the same
calculated energies. The conformer D is more stable than the
Figure 8. Rotational barriers for the aromatic substrate 1 for rotations
around the C1 N bond.
of relatively hindered rotations, mainly as a result of
interactions between the aromatic ring and the ester group.
The substrate was crystallised in Et2O and its crystal
structure was determined by X-ray structural analysis (Fig-
ure 9).[21] When compared with molecular-modelling calcula-
1
other three by more than 3 kJmol . Thus, we can assume that
conformer D represents the most probable structure of this
substrate.
Figure 7 shows the rotational barriers as a function of the
rotation angle about the bond C1 C2. The two energy minima
correspond to the isomers D and B. There are two very high
Figure 9. Comparison of the crystallographic form of substrate 1 obtained
by X-ray analysis (right) and the most stable conformer obtained by
molecular-modelling calculation (left).
Figure 7. Rotational barriers for the aromatic substrate 1 for rotations
around the C2 C1 bond.
tions, the structure obtained is very close to the most stable
conformation D. The only difference observed is the value of
the dihedral angle formed between the average plane of the
pyroglutamate ring (C9-C10-C11-C12-N) and the aromatic
ring. This is illustrated in Figure 9, with the representation of
energy barriers for total rotation about this bond which
changes from one isomer to the other. This is attributed to
significant steric hindrances between the oxygen of the amido
ˆ
function (C1 O) and the two ortho substitutents of the
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Asymmetric Synthesis
949±958
the aromatic substrate in profile and the ester group pointing
to the back left. From molecular modelling, the aromatic ring
shows a deviation of 1058 relative to the plane of the
pyroglutamate ring, while it is shown to be twisted by 608 in
the X-ray analysis. This implies that the oxygen atom O4
attached to the pyroglutamate is oriented towards the
aromatic ring in two different directions, either below the
C2 C7 bond, or below the C2 C3 bond, as illustrated by the
distance between the non-bonded atoms O4 and C3 (3.92 and
2.95 Š, respectively) and O4 and C7 (2.86 and 3.76 Š,
respectively). These observed differences can be explained
by considering that molecular modelling calculates the energy
of the molecule in the gas phase rather than in the solid state.
These small differences are not crucial and do not modify the
conclusions that can be drawn on the approach of the
molecule to the metallic surface. In both cases, one of the
faces of the aromatic ring is shielded by the presence of the
ligand.
aromatic ring can only adsorb at the unshielded face and the
cis addition of hydrogen on this adsorbed intermediate gives
rise to the preferential formation of 3b; this is in agreement
with the experimental results. Indeed, results given in Tables 1
and 3 show that high diastereoselectivities were obtained.
The selectivity data given in Table 1 for the Rh/C and Rh/
Al2O3 catalysts show that the asymmetric induction is higher
than for the alumina-supported catalyst. TEM and XPS
studies have shown that in Rh/Al2O3, the rhodium particles
have a flat morphology and that there are partially oxidised
species present.[22] As proposed in the case of prolinate
auxiliary,[22] this promoting effect may be attributed to a
stronger interaction between the rhodium atoms with a low
valence state on alumina and the oxygenated groups of the
ester, which optimises the adsorptive effect.
The nature of the ester group in the pyroglutamate was
found to have only a small positive effect on the diastereo-
selectivity (Table 2). This can be easily explained by the
observation that in the most stable conformation of the
substrate 1 (R ˆ Me), the ester is in an external position
relative to the aromatic ring (Figure 9). Therefore, one may
expect that the ester will exert only a small steric constraint
during adsorption.
Solution 1H NMR spectrometry confirmed the existence of
only one stable conformer. Indeed, in the substrate with the
1
prolinate auxiliary, a splitting was observed in the H NMR
spectrum attributed to the existence of the substrate in the
form of two stable conformers of nearly the same energy in a
80/20 ratio.[12] In contrast, in the 1H spectrum of the
pyroglutamate substrate (Figure 10), the line widths were
With respect to the nature of the metal (rhodium or
ruthenium), in the absence of the amine EDCA, a higher
diastereoselectivity was observed in
the presence of ruthenium support-
ed on active carbon than in the
presence of rhodium (74% com-
pared with 50%, in favour of 3b,
Tables 1 and 2). The mode of ad-
sorption of the aromatic substrate
onto the unshielded face of the
aromatic ring dictates the major
configuration of the hydrogenation
product. However, as already noted
with the prolinate auxiliary,[22] an
additional anchoring interaction
between the oxygen atoms (ester
group and benzoic carbonyl) and
the ruthenium metallic surface,
which is more electropositive than
rhodium, may still promote a pref-
erential adsorption of the molecule
Figure 10. 1H NMR spectrum at 200 MHz of substrate 1 (R ˆ Me).
onto one specific face. This leads to
narrow and integrations were assigned unambiguously, which
suggests that only one diastereoisomer, or a very rapidly
equilibrating mixture of diastereoisomers of 1, exist in
solution at room temperature.
From the results of the three techniques described above, it
may be assumed that substrate 1 presents the molecular
structure of conformer D.
an enhancement of the diastereoselectivity.
Interestingly, the addition of EDCA to the Rh/C catalysts
greatly improved the de (Table 1). There is some evidence
that the amine molecules adsorb onto the metal surface, so
they may exert a supplementary favourable orientating effect.
As a result of the competitive adsorption between the
substrate and the amine, the conversion of the pyroglutamate
was not complete. Thus, the addition of EDCA, in the
presence of the ruthenium catalyst only had a weak beneficial
effect (Table 3). These findings are supported by our obser-
vation of a smaller decrease in the initial reaction rate as the
amine was adsorbed onto the catalyst, which indicated a lesser
covering of ruthenium by the amine as compared with
rhodium on carbon.
Interpretation of the selectivity data: Figure 9 shows that one
face of the aromatic ring 1 is shielded by the carbonyl group.
We now consider the adsorption of the aromatic ring on the
metal surface, which generally proceeds by p-bonding. The
adsorption of the shielded face of the aromatic ring is
unfavourable as a result of steric hindrance. Hence, the
Chem. Eur. J. 2000, 6, No. 6
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955

M. Besson et al.
FULL PAPER
6.2 Hz, 1H; CHMe2), 4.15 (m, 1H; CHN), 2.5 ± 2.1 (m, 4H; CH2 CH2),
1.20 (d, 3J(H,H) ˆ 6.2, 6H; CHMe2); 13C NMR (50 MHz, CDCl3): d ˆ 180.0
(C), 171.8 (C), 69.3 (CH), 55.8 (CH2), 30.7 (CH2), 24.9 (CH2), 21.7 (CH3);
Conclusions
Cis-2-methyl cyclohexane carboxylic acids have been pre-
pared with diastereoisomeric excesses of up to 96%. The
efficiency of the pyroglutamate auxiliary relative to prolinate
is attributed to the presence of the carbonyl group. A
combination of molecular-modelling calculations, NMR spec-
troscopy and X-ray analysis strongly suggest that substrate 1
exists as one single conformation in which one face of the
aromatic ring is shielded by the carbonyl group of the
pyroglutamate auxiliary. To minimise the steric requirements
imposed by the adsorption of the aromatic substrate on the
catalyst surface, the adsorption must occur onto the unshield-
ed face; this induces high diastereoselectivities for the hydro-
genation of the aromatic ring. In all experiments, the hydro-
genated compound with configuration (1S,2R,2'S) was ob-
tained.
ˆ
IR (film): nÄ ˆ 3475 (N H), 2986 (C H), 2933 (C H), 1755 (C O), 1668
(C O) cm 1; [a]2D4: ‡6 (c ˆ 5 in methanol); elemental analysis calcd (%) for
ˆ
C8H13O3N: C 56.14, H 7.60, N 8.19; found C 56.12, H 7.81, N 8.19.
(S)-tert-Butyl pyroglutamate (5, R ˆ tBu): Perchloric acid 70% (3 mL,
0.7 equiv) was added dropwise to a solution of pyroglutamic acid (12.9 g,
0.1 mol) in tert-butyl acetate (185 mL, 11 equiv). The solution was stirred
overnight at room temperature then NaHCO3 was added slowly until pH 6
was reached. The aqueous layer was extracted with Et2O (100 mL) then
AcOEt (100 mL). The combined extracts were dried (MgSO4) and
concentrated under vacuum to give
a yellowish powder which was
recrystallised from Et2O to yield white crystals (10.5 g, 57%).
1
M.p. 1028C; H NMR (200 MHz, CDCl3): d ˆ 7 (s, 1H; NH); 4.1 (m, 1H;
CHN), 2.0 ± 2.5 (m, 4H; CH2 CH2), 1.4 (s, 9H; 3 CH3); 13C NMR (50 MHz,
CDCl3): d ˆ 178.3 (C), 171.3 (C), 82.2 (C), 56.3 (CH), 29.5 (CH2), 28.0
(CH3), 24.9 (CH2); IR (film): nÄ ˆ 3260 (N H), 2989 (C H), 2969 (C H),
2946 (C H), 1737 (C O), 1679 (C O) cm 1; [a]D24: ‡11 (c ˆ 3 in methanol);
elemental analysis calcd (%) for C9H15O3N: C 58.38, H 8.11, N 7.57; found
C 58.67, H 8.20, N 7.51.
ˆ
ˆ
A change in the size of the ester groups did not greatly
influence the selectivity, since this ester group is located in an
outer position relative to the aromatic ring and does not
participate much in the adsorption.
Synthesis of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates (1): The syn-
thesis of 1 (R ˆ Me) is described below as a representative example.
(S)-Methyl-N-(2-methylbenzoyl)pyroglutamate (1, R ˆ Me): Triethyl-
amine (19.5 mL, 2 equiv) and followed by o-toluoyl chloride (11 mL,
A small change in the structure of the chiral auxiliary
(pyroglutamic acid versus proline) dramatically improved the
de of the hydrogenation reaction (max. ꢀ95% and 68%,
respectively). Two phenomena are responsible for this higher
selectivity: firstly, only one conformer of the substrate is
1.2 equiv) were added dropwise to
a stirred solution of (S)-methyl
pyroglutamate (5 (R ˆ Me); 10 g) in toluene (130 mL) at 08C under argon.
The mixture was stirred for 5 h at 808C and then cooled to room
temperature. The organic layer was treated with saturated NaHCO3 (2 Â
20 mL), NaCl (20 mL), then dried (MgSO4) and concentrated to give a
yellowish powder. The product was recrystallised from Et2O to yield white
needles (15 g, 82%). M.p. 1088C; 1H NMR (200 MHz, CDCl3): d ˆ 7.2 (m,
4H; CHarom), 5.0 (dd, 3J(H,H) ˆ 3.4 Hz, 9.0 Hz, 1H; CHCOO), 3.8 (s, 3H;
COOCH3), 2.7 ± 2.0 (m, 4H; CH2 CH2), 2.4 (s, 3H; ArCH3); 13C NMR
(50 MHz, CDCl3): d ˆ 173.0 (C), 171.5 (C), 170.4 (C), 135.5 (C), 135.0 (C),
130.4 (CH), 130.2 (CH), 126.9 (CH), 125.3 (CH), 57.9 (CH), 52.8 (CH3),
31.6 (CH2), 21.6 (CH2), 19.2 (CH3); IR (film): nÄ ˆ 3480 (N H), 3041 (C H),
ˆ
formed during its synthesis and secondly, the additional C O
group significantly increased the steric hindrance of the
aromatic face. The pyroglutamate auxiliary should have a
large potential for other diastereoselective hydrogenations of
aromatic substrates on metal catalysts.
2960 (C H), 2928 (C H), 1751 (C O), 1679 (C O) cm 1; tR ˆ 16.9 min; MS
ˆ
ˆ
(70 eV, EI): m/z (%): 91, 119 (100%), 261 [M ]; [a]D24
:
29 (c ˆ 1 in
‡
chloroform); elemental analysis calcd (%) for C14H15O4N: C 64.37, H 5.75,
N 5.36; found C 64.62, H 5.77, N 5.32.
Experimental Section
(S)-Ethyl-N-(2-methylbenzoyl)pyroglutamate (1, R ˆ Et): Yield: 47%;
white crystals; m.p. 528C; 1H NMR (200 MHz, CDCl3): d ˆ 7.45 (m, 4H;
1H and 13C NMR spectra were recorded on AC100 and AC200 Bruker
spectrometers and referenced to the residual solvent (CDCl3: dH ˆ 7.24,
dC ˆ 77). FT-IR spectra were recorded on a Bruker Vector22 apparatus.
Elemental analyses were performed at the ªService Central dꢁAnalyseº,
CNRS. Gas chromatography (GC) was performed on a Shimadzu GC14A
apparatus with a J&W DB1701 column (30 m, Tinj ˆ 2708C, Tdet ˆ 2908C,
Toven ˆ 1708C: 1 min, then 58Cmin 1 up to 2608C, then 2608C for 25 min).
3
CHarom.), 5.0 (m, 1H; CHCOO), 4.2 (q, J(H,H) ˆ 7.0 Hz, 2H; COOCH2),
3
2.8 ± 2.0 (m, 4H; CH2 CH2), 2.3 (s, 3H; ArCH3), 1.3 (t, J(H,H) ˆ 7.0 Hz,
3H; CH3); 13C NMR (50 MHz, CDCl3): d ˆ 173.3 (C), 171.3 (C), 170.6 (C),
135.7 (C), 135.3 (C), 130.6 (CH), 130.4 (CH), 127.1 (CH), 125.6 (CH), 62.2
(CH2), 58.3 (CH), 31.9 (CH2), 21.9 (CH2), 19.5 (CH3), 14.4 (CH3); IR (film):
nÄ ˆ 3629 (N H), 3495 (N H), 3064 (C H), 2983 (C H), 2935 (C H), 1754
(C O), 1681 (C O) cm 1; tR ˆ 18.2 min; MS (70 eV, EI): m/z (%): 91, 119
ˆ
ˆ
Synthesis of the alkylpyroglutamates: Ethyl and octyl pyroglutamates are
commercially available. The preparation of the other esters is described
below.
‡
(100%), 202, 275 [M ]; [a]D24
:
35 (c ˆ 1 in chloroform); elemental analysis
calcd (%) for C15H17O4N: C 65.38, H 6.18, N 5.09; found C 65.91, H 6.32, N
4.99.
(S)-Methyl pyroglutamate (5, R ˆ Me): SOCl2 (34 mL, 5 equiv) was added
dropwise to a stirred solution of l-pyroglutamic acid (12 g, 0.09 mol) in
MeOH (130 mL) under argon at 08C. The solution was refluxed for 1.5 h
and excess SOCl2 was removed. The residue was distilled (1458C, 3.5 mbar)
(S)-iso-Propyl-N-(2-methylbenzoyl)pyroglutamate (1, R ˆ iPr): Yield:
70%; white powder; m.p. 708C; 1H NMR (200 MHz, CDCl3): d ˆ 7.30
(m, 4H; CHarom.), 5.1 (sextet, 3J(H,H) ˆ 6.2 Hz, 1H; COOCH), 4.9 (dd,
3J(H,H) ˆ 3.5 Hz, 8.9 Hz, 1H; CHCOO), 2.7 ± 2.0 (m, 4H; CH2 CH2), 2.4
1
to give a pure pale yellow oil (10.2 g, 76%). H NMR (100 MHz, CDCl3):
3
(s, 3H; ArCH3), 1.3 (d, J(H,H) ˆ 6.2 Hz, 3H; CH3); 13C NMR (50 MHz,
d ˆ 7.5 (s, 1H; NH), 3.9 (dd, 3J(H,H) ˆ 4.4 Hz, 8.2 Hz, 1H; CHN), 3.4 (s,
3H; CH3), 1.7 ± 2.1 (m, 4H; CH2 CH2); 13C NMR (25 MHz, CDCl3): d ˆ
178.4 (C), 172.7 (C), 55.3 (CH3), 52.0 (CH2), 29.0 (CH2), 24.5 (CH2); IR
CDCl3): d ˆ 173.1 (C), 170.6 (C), 170.5 (C), 135.4 (C), 135.2 (C), 130.3
(CH), 130.1 (CH), 126.9 (CH), 125.3 (CH), 69.6 (CH2), 58.3 (CH), 31.6
(CH2), 21.8 (CH2), 21.7 (CH3), 21.6 (CH3), 19.2 (CH3); IR (film): nÄ ˆ 3475
(film): nÄ ˆ 3230 (N H), 2957 (C H), 1744 (C O) cm 1; [a]D24: ‡10 (c ˆ 6 in
ˆ
‡
ˆ
(N H), 3054 (C H), 2986 (C H), 2933 (C H), 1755 (C O), 1668
methanol); MS (70 eV, E.I.): m/z (%): 56, 84 (100), 143 [M ]; elemental
(C O) cm 1; [a]2D4
:
41 (c ˆ 1 in chloroform); elemental analysis calcd
ˆ
analysis calcd (%) for C6H9O3N: C 50.35, H, 6.29, N 9.79; found C 50.06, H
6.16, N 9.74.
(%) for C16H19O4N: C 66.44, H 6.57, N 4.84; found C 66.60, H 6.62, N 4.84.
(S)-iso-Propyl pyroglutamate (5, R ˆ iPr): SOCl2 (14 mL, 5 equiv) was
added dropwise to a stirred solution of l-pyroglutamic acid (5 g, 0.04 mol)
in iPrOH (100 mL) under argon at 08C and the solution was refluxed for
90 min. Excess SOCl2 and iPrOH were removed by filtration. The solid was
recrystallised in iPr2O to yield beige needles (5.6 g, 85%). M.p. 688C;
1H NMR (200 MHz, CDCl3): d ˆ 7 (s, 1H; NH), 5 (sextet, 3J(H,H) ˆ
(S)-tert-Butyl-N-(2-methylbenzoyl)pyroglutamate (1, R ˆ tBu): Yield:
87%; white powder; m.p. 868C; 1H NMR (200 MHz, CDCl3): d ˆ 7.30
(m, 4H; CHarom), 4.8 (dd, 3J(H,H) ˆ 3.5 Hz, 8.9 Hz, 1H; CHCOO), 2.8 ± 2.0
(m, 4H; CH2 CH2), 2.4 (s, 3H; ArCH3), 1.5 (s, 9H; CH3); 13C NMR
(50 MHz, CDCl3): d ˆ 173.2 (C), 170.3 (C), 170.1 (C), 135.4 (C), 135.2 (C),
130.3 (CH), 130.0 (CH), 126.9 (CH), 125.2 (CH), 82.2 (C), 58.8 (CH), 31.6
956
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0606-0956 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 6

Asymmetric Synthesis
949±958
(CH2), 21.5 (CH2), 19.2 (CH3); IR (film): nÄ ˆ 3500 (N H), 3300 (N H),
ments used 2.25 mmol of substrate dissolved in 130 ml ethanol. In order to
improve the selectivity, some experiments were carried out with the
addition of EDCA (ethyldicyclohexylamine). The conversions and selec-
tivities were determined from GC data.
1
ˆ
ˆ
3050 (C H), 2977 (C H), 2950 (C H), 1751 (C O), 1680 (C O) cm
;
[a]2D4
C17H21O4N: C 67.33, H 6.93, N 4.62; found C 67.76, H 7.02, N 4.72.
:
50 (c ˆ 1 in chloroform); elemental analysis calcd (%) for
Molecular-modelling calculations: Molecular-modelling calculations were
performed using Sybil software. Initial conformational structure for the
diastereoisomer was constructed and the geometries were minimised with
the MM2 force field. The Cartesian coordinates that were generated were
converted to graphics to allow examination from alternative perspectives.
(S)-Octyl-N-(2-methylbenzoyl)pyroglutamate (1, R ˆ n-octyl): Yield:
67%; brown oil; 1H NMR (200 MHz, CDCl3): d ˆ 7.30 (m, 4H; CHarom),
4.9 (dd, 3J(H,H) ˆ 3.1, 8.9 Hz, 1H; CHCOO), 4.2 (t, 3J(H,H) ˆ 6.6 Hz, 2H;
COOCH2), 2.7 ± 2.0 (m, 4H; CH2 CH2), 2.4 (s, 3H; ArCH3), 1.6 (m, 2H;
CH2), 1.3 (m, 10H; 5CH2), 0.9 (m, 3H; CH3); 13C NMR (50 MHz, CDCl3):
d ˆ 172.8 (C), 170.8 (C), 170.0 (C), 135.2 (C), 134.9 (C), 130.0 (CH), 129.8
(CH), 126.7 (CH), 125.0 (CH), 63.7 (C), 57.8 (CH), 31.5 (CH2), 21.3 (CH2),
28.9 (CH2), 28.3 (CH2), 25.5 (CH2), 22.4 (CH2), 22.3 (CH2), 21.4 (CH2), 18.9
Acknowledgements
(CH3), 13.8 (CH3); tR ˆ 32.2 min; MS (70 eV, EI): m/z (%): 91, 119 (100%),
‡
202, 359 [M ]; [a]D24
:
23 (c ˆ 1 in chloroform); elemental analysis calcd
Â
The authors thank Prof. Rene Faure (University Claude Bernard-Lyon 1)
(%) for C21H29O4N: C 70.19, H 8.08, N 3.90; found C 69.82, H 8.20, N 3.31.
for the X-ray structure determination. The Ministry of National Education
and Research is acknowledged for a grant (SN).
2-Methyl-1-cyclohex-2-ene carboxylic acid: Ethyl 2-methyl-1-cyclohex-2-
ene carboxylate (2 g, 12 mmol) was added to a solution of KOH (1.13g,
1.7 equiv) in MeOH/H2O (6:1, 12 mL).[23] The solution was refluxed for
4 H, then cooled to room temperature and washed with Et2O (2 Â 20 mL).
The aqueous phase was acidified with HCl (pH 1) and extracted with Et2O
(4 Â 30 mL). The combined organic phases were dried over MgSO4 and
concentrated to yield a white solid (1.4 g, 82%). M.p. 808C; 1H NMR
(100 MHz, CDCl3): d ˆ 11.9 (s, COOH), 2.4 ± 1.4 (m, 8H; CH2), 2.04 (s, 3H;
CH3).
[1] The Merck Index, 12th ed., Merck Research Lab, Merck, 1996.
[2] S. Hanessian, Total Synthesis of Natural Products: The ªChironº
Approach, Pergamon, Oxford, 1984, p. 163.
[3] J. K. Whitesell, Chem. Rev. 1992, 92, 953.
[4] P. Thom, P. Kocienski, K. Jarowicki, Synthesis, 1992, 475.
[5] R. L. Gu, C. J. Sih, Tetrahedron Lett. 1990, 31, 3287.
[6] Y. Izumi, Adv. Catal. 1983, 32, 215; T. Ozawa, T. Harada, A. Tai, Catal.
Today 1997, 37, 465.
[7] H. U. Blaser, H. P. Jalett, M. Müller, M. Studer, Catal. Today 1997, 37,
441; A. Baiker, Stud. Surf. Sci. Catal. 1996, 101, 51; A. Baiker, H. U.
Blaser, in Handbook of Catalysis, Vol. 5 (Eds.: G. Ertl, H. Knözinger,
J. Weitkamp), VCH, Weinheim, 1997, p. 2442; M. Schürch, T. Heinz,
R. Aeschimann, T. Mallat, A. Pfaltz, A. Baiker, J. Catal. 1998, 173,
187; R. L. Augustine, S. K. Tanielyan, L. K. Doyle, Tetrahedron:
Asymmetry 1993, 4, 1803; J. L. Margitfalvi, E. Tfirst, J. Mol. Catal.
1999, 139, 81.
[8] K. Harada, Asymmetric Synthesis, Vol. 5, Chiral Catalysis, Academic
Press, Orlando, 1985, p. 345.
[9] M. Besson, C. Pinel, Topics in Catalysis 1998, 5, 25.
[10] K. Nasar, M. Besson, P. Gallezot, F. Fache, M. Lemaire, in Chiral
Reactions in Heterogeneous Catalysis (Eds.: G. Jannes, V. Dubois),
Plenum, New York, 1995, p. 141.
(S)-Methyl-N-(2-methyl-cyclohex-1-enecarbonyl)pyroglutamate (2): SOCl2
(0.2 mL, 4 equiv) was added to a solution of 2-methyl-1-cyclohex-2-ene
carboxylic acid (100 mg, 7 mmol) in CHCl3 (2 mL) at 08C under argon. The
solution was stirred overnight and the solvents were removed under
vacuum. The crude product was used in the next step without purifica-
tion. (S)-Methyl-N-(2-methylbenzoyl)pyroglutamate (1 (R ˆ Me), 100 mg,
7 mmol) in toluene (7 mL) was placed in a three-necked round-bottomed
flask. Triethylamine (0.3 mL, 3 equiv) followed by the crude acid chloride
were added and the mixture was stirred for 3 h at 708C. The solution was
washed with NaHCO3 (2 Â 10 mL) then NaCl (2 Â 10 mL), dried (MgSO4)
and concentrated under vacuum to yield 100 mg of a brownish oil. The
mixture was analysed by GC/MS without purification; tR ˆ 14.6 min; MS
‡
(70 eV, EI): m/z (%): 79, 122 (100), 265 [M ].
(S)-Methyl-N-(2-methyl-cyclohexanecarbonyl)pyroglutamate (3a,b/4a,b;
R ˆ Me) (synthetic route): SOCl2 (4 mL, 4 equiv) was added dropwise to
a solution of a commercial mixture (cis:trans ˆ 85:15) of 2-methyl-cyclo-
hexane carboxylic acid (2 g, 14 mmol) in CHCl3 (10 mL) at 08C under
argon. The mixture was stirred overnight at room temperature and the
solvents were removed. The yellow oil was used without purification in the
next step. (S)-Methyl-N-(2-methylbenzoyl)pyroglutamate (1 (R ˆ Me), 2 g,
14 mmol) in toluene (20 mL) was placed in a three-necked round-bottomed
flask. Triethylamine (3.8 mL, 2 equiv) followed by the crude acid chloride
were added and the mixture was stirred for 3 h at 808C. The solution was
washed with NaHCO3 (2 Â 10 mL) then NaCl (2 Â 10 mL), dried (MgSO4)
and concentrated under vacuum to yield 2 g of a brownish oil. The GC/MS
analysis of the crude product showed 3 signals (tR ˆ 13.2, 13.7, 14.3 min,
respective integration: 11:50:39). Recrystallisation from cyclohexane
yielded enriched cis isomer (respective integration: 7:87:6). Selected data
of the main compound [3b (R ˆ Me)]: 1H NMR (100 MHz, CDCl3): d ˆ
4.68 (dd, 3J(H,H) ˆ 2.4 Hz, 9.3 Hz, 1H; CHCOO), 3.74 (s, 3H; COOCH3),
2.8 ± 1.3 (m, 14H), 0.83 (d, 3J(H,H) ˆ 7.1 Hz, 3H; CH3); 13C NMR (25 MHz,
CDCl3): d ˆ 176.4 (C), 173.8 (C), 171.9 (C), 135.4 (C), 58.3 (CH), 52.6
(CH3), 32.3 (CH2), 31.9 (CH2), 30.8 (CH), 24.2 (CH2), 23.4 (CH2), 21.6
(CH2), 21.2 (CH2), 15.2 (CH3); MS (70 eV, EI): m/z (%): 124, 144 (100), 185,
[11] C. Exl, E. Ferstl, H. Hönig, R. Rogo-Kohlenprath, Chirality, 1995, 7,
211.
[12] M. Besson, B. Blanc, M. Champelet, P. Gallezot, K. Nasar, C. Pinel, J.
Catal. 1997, 170, 254.
[13] V. S. Ranade, G. Consiglio, R. Prins, Catal. Lett. 1999, 58, 71.
[14] V. S. Ranade, R. Prins, J. Catal. 1999, 185, 479.
Â
Â
Â
[15] A. Tungler, Z. P. Karancsi, V. Hada, L. Hegedus, T. Mathe, L.
Szepessy, Poster 14, 5th International Symposium On Heterogeneous
Catalysis and Fine Chemicals, Lyon (France), 1999.
[16] M. Besson, C. Pinel, S. Neto, F. Delbecq, N. Douja, P. Gallezot,
Poster 2, 5th International Symposium On Heterogeneous Catalysis
and Fine Chemicals, Lyon (France), 1999.
[17] M. Besson, P. Gallezot, S. Neto, C. Pinel, unpublished results.
[18] M. Besson, P. Gallezot, S. Neto, C. Pinel, Chem. Commun. 1998, 1431.
[19] J. Buckingham, S. M. Donaghy, in Dictionary of Organic Compounds,
5th ed., Chapman and Hall, New York, 1982.
[20] A mixture of the isomers was synthesised from commercial 2-methyl
cyclohexane carboxylic acid (cis:trans ˆ 85:15). The GC analysis
showed three peaks at t1, t2 and t3, with relative surface areas of 11,
50 and 39%, respectively. It is quite reasonable to propose the
following assignment: the peak at t1 is trans-1 (the first trans isomer off
the column), that at t2 is cis-1 ‡ trans-2 and at t3 it is cis-2, namely there
is a superimposition of one of the cis isomers and one of the trans
isomers. Furthermore, the reaction medium after hydrogenation of 1
(R ˆ Me), which gave three peaks of relative surface areas 5, 65 and
30%, was hydrolysed in HCl (6n). After extraction with ethyl acetate,
the analysis of the 2-methyl cyclohexane carboxylic acid thus formed,
‡
198, 208, 267 [M ].
Catalysts: The catalysts used in the hydrogenation were 3.6% Rh/C
(Aldrich 20,616-4), 3.7% Rh/Al2O3 (Aldrich 37,971-9), 5% Ru/C (Al-
drich 28,147-6) and 3.5% Ru/Al2O3 (Aldrich 22,853-2). 2.8% Ru/TiO2 was
supplied by Engelhard (Q500-069D). High-resolution electron microscopy
showed that most of the rhodium and ruthenium particles in the catalysts
were in the size range 1 ± 4 nm and homogeneously distributed inside the
grains. The ruthenium catalysts were pre-treated at 3008C under hydrogen
atmosphere and transferred to the reactor without exposure to air.
yielded
a cis:trans ratio of 96:4, which demonstrates that the
Hydrogenation experiments: The hydrogenation of substrate 1 was carried
out in a stainless steel autoclave equipped with a magnetically driven
turbine stirrer under 50 MPa and at room temperature. Standard experi-
concentration of the trans isomers in the reaction medium was very
low (always <5%). The uncertainty, which would result regarding the
intensity of peak for cis-1, would therefore be negligible. Finally, the
Chem. Eur. J. 2000, 6, No. 6
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957

M. Besson et al.
FULL PAPER
hydrolysis of a hydrogenation medium, in which no peak with
retention time t1 was detected, allowed us to verify that there was
actually no trans-2-methyl cyclohexane carboxylic acid produced.
[21] Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-125671. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK
(fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[22] M. Besson, P. Gallezot, C. Pinel, S. Neto, in Studies in Surface Science
and Catalysis, Heterogeneous Catalysis and Fine Chemicals, Vol. 108
(Eds.: H. U. Blaser, A. Baiker, R. Prins), Elsevier, Amsterdam, 1997,
p. 215.
[23] Prepared according to F. W. Sum, L. Weiler, Can. J. Chem. 1979, 57,
1431.
Received: June 16, 1999 [F1854]
958
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Chem. Eur. J. 2000, 6, No. 6