Table 1. Asymmetric Hydrogenation of Dimethyl Itaconate
Table 2. Asymmetric Hydrogenation of Dimethyl Itaconate
with Monophosphite Ligandsa
Using [Rh(COD)
a
Using [Rh(COD)
2
]BF
4
2
6
]SbF with Monophosphite Ligands
b
% eeb,c
b
% eeb,c
entry
ligand
conv (%)
entry
ligand
solvent
conv (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4a
4b
5a
5b
6a
6b
7a
7b
6c
7c
8a
8b
9a
90
100
97
14.0 (R)
96.5 (S)
19.0 (R)
96.4 (S)
25.0 (R)
92.0 (S)
44.0 (S)
93.0 (R)
24.3 (R)
32.0 (S)
n.a.
1
2
3
4
5
6
7
8
9
4a
5a
6a
7a
6c
6c
7c
7c
8a
8a
9a
9a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
CH2Cl2
100
100
100
100
100
100
100
100
100
100
100
100
16.4 (R)
22.5 (R)
14.5 (R)
9.3 (S)
94.4 (R)
98.9 (R)
97.6 (S)
98.7 (S)
97.8 (R)
99.6 (R)
99.0 (R)
99.1 (R)
100
100
100
100
100
3.5
4.3
<1
1
1
1
1
10
11
12
<1
<1
n.a.
n.a.
ClCH2CH2Cl
a
The reaction was performed at 50 °C and 100 psi (6.8 atm) of H2 for
20 h [substrate (0.5 mmol, 0.1 M)/Rh(COD)2SbF6/ligand ) 200:1:2].
a
The reaction was performed in CH2Cl2 at 23 °C and 100 psi (6.8 atm)
of H2 for 20 h [substrate (0.5 mmol, 0.1 M)/Rh(COD)2BF4/ligand ) 200:
:2]. Conversion and enantiopurity were determined by GC on a Supelco
Beta Dex-225 column. The absolute configuration was determined by
comparing the GC spectra with those of authentic samples.
b
Conversion and enantiopurity were determined by GC on a Supelco Beta
Dex-225 column. c The absolute configuration was determined by comparing
GC spectra with those of authentic samples.
b
1
c
bearing aryloxy moieties (4a and 5a) (entries 1 and 2) or
(-)-menthyloxy moieties (6a and 7a) (entries 3 and 4) do
not show any improvement. Nevertheless, the catalytic
activity of these ligands (4a-7a) is greatly improved, giving
the product in quantitative yield in each case.
did not further improve the enantioselectivity as compared
to that achieved by the ligands with an achiral aryloxy moiety
(4b and 5b) (entries 2, 4, 6, and 8).
The reactions using 6b (S-biphenyl) and 7b (R-biphenyl),
which have the same (-)-menthyloxy moiety, gave (S)-
methylsuccinate (92% ee) and (R)-methylsuccinate (93% ee),
respectively (entries 6 and 8). Thus, the influence of the chiral
alkoxy moiety of the ligand on enantioselectivity is found
to be almost negligible.
Solvents used in this reaction exerted dramatic effects on
the enantioselectivity. For example, when THF, MeOH,
EtOAc, or CHCl was used as the solvent, no enantioselec-
3
tivity was observed. Similar results have recently been
reported by van der Berg et al. for their BINOL-based
It is worth mentioning that the substituents at the 3 and 3′
15
phosphoramidite ligand. Appropriate solvents for this
2
positions (R ) H or t-Bu) exert marked differences in the
hydrogenation reaction so far appear to be dichloromethane
and 1,2-dichloroethane, and the use of 1,2-dichloroethane
has achieved the best enantioselectivity in all cases examined
direction and the extent of asymmetric induction. Thus, the
ligands with a hydrogen at the 3 and 3′ positions (4b, 5b,
6b, and 7b) uniformly show excellent enantioselectivity,
(entries 6, 8, 10, and 12).
giving (S)-methylsuccinate [(R) for 7b], while those with a
tert-butyl group at the 3 and 3′ positions afford (R)-
methylsuccinate [(S) for 7a] with only 14-44% ee.
The ligands bearing a bulky chiral secondary alkoxy group
on the phosphorus (8a, 8b, and 9a) virtually do not show
any appreciable activity under the same conditions, although
the ligands with a (-)-phenylmenthyloxy group (6c and 7c)
show very low conversion and low to moderate enantiose-
lectivity (entries 9-13).
It is believed that two molecules of a monophosphite
ligand will coordinate with a Rh metal to form an active
1b,16
catalyst species.
of ligand 7b to Rh under the conditions in Table 1 gave
R)-methylsuccinate with the same enantiopurity (93% ee)
However, the reaction using only 1 equiv
(
in quantitative yield. In turn, the conversion and enantiose-
lectivity significantly decreased (7.0% conversion, 58% ee)
when the ligand/Rh ratio was increased to 3. A similar
phenomenon has recently been reported in the reaction of a
Next, we switched the Rh-catalyst precursor from [Rh-
16
dehydroamino acid using a monophosphoramidite ligand.
(
COD)
at 50 °C and 100 psi (6.8 atm) of H
summarized in Table 2. As Table 2 shows, the bulky ligands
6c, 7c, 8a, and 9a), which gave rather poor results or did
2
]BF
4
to [Rh(COD)
2
]SbF
6
and carried out the reactions
More interestingly, the ligand/Rh ratio did not make any
difference in the conversion and enantioselectivity when
using bulky ligands such as 7c under the conditions in Table
. Thus, the reactions using 7c in 1,2-dichloroethane gave
S)-methylsuccinate in complete conversion and 98.7% ee
with the ligand/Rh ratio of 1, 2, or 3. Detailed mechanistic
2
in CH Cl . Results are
2
2
(
2
(
not show catalytic activity under the conditions summarized
in Table 1, have achieved excellent enantioselectivity (up
to 99.6% ee) and 100% conversion (entries 5-12). Thus, a
remarkable effect of the counteranion on the catalytic activity
as well as enantioselectivity is observed. However, it should
be noted that the remarkable improvement in enantioselec-
tivity is observed only for the ligands bearing very bulky
chiral alkoxy moieties (6c, 7c, 8a, and 9a), and the ligands
(15) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.;
Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars,
C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J.
W.; de Vries, J. G. AdV. Synth. Catal. 2003, 308.
(16) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961.
Org. Lett., Vol. 5, No. 21, 2003
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