Highly efficient asymmetric hydrogenation of 2-methylenesuccinamic acid using a Rh-DuPHOS catalyst

Article abstract of DOI:10.1021/op0256183

An extremely efficient route to highly enantiomerically enriched 2-methylsuccinamic acid via asymmetric hydrogenation has been developed. By using [(S,S)-Et-DuPHOS Rh COD]BF₄ as the precatalyst under a set of broadly optimised process parameters, (R)-2-methylsuccinamic acid was obtained in 96% ee at a substrate-to-catalyst ratio (S/C) of 100000 (average turnover frequency ～13000 h^-1). The exclusion of chloride-containing contaminants in the substrate was found to be crucial in obtaining exceptionally low catalyst loadings. This material could be upgraded with a single-crystal digestion to yield (R)-2.methylsuccinamic acid in >99.5% ee containing less than 1 ppm rhodium.

Full text of DOI:10.1021/op0256183

Organic Process Research & Development 2003, 7, 407−411
Highly Efficient Asymmetric Hydrogenation of 2-Methylenesuccinamic Acid
Using a Rh-DuPHOS Catalyst
Christopher J. Cobley,* Ian C. Lennon, C e´ line Praquin, and Antonio Zanotti-Gerosa
Dowpharma, Chirotech Technology Ltd., A Subsidiary of The Dow Chemical Company, Cambridge Science Park,
Unit 321, Milton Road, Cambridge CB4 0WG, U.K.
Robert B. Appell, Christian T. Goralski, and Angela C. Sutterer
Dowpharma, The Dow Chemical Company, 1710 Building, Midland, Michigan 48674, U.S.A.
Abstract:
Scheme 1. Synthesis of (R) or (S)-methylsuccinamic acid
via asymmetric hydrogenation
An extremely efficient route to highly enantiomerically enriched
2
-methylsuccinamic acid via asymmetric hydrogenation has
been developed. By using [(S,S)-Et-DuPHOS Rh COD]BF as
4
the precatalyst under a set of broadly optimised process
parameters, (R)-2-methylsuccinamic acid was obtained in 96%
ee at a substrate-to-catalyst ratio (S/C) of 100000 (average
-
1
turnover frequency ∼13000 h ). The exclusion of chloride-
containing contaminants in the substrate was found to be crucial
in obtaining exceptionally low catalyst loadings. This material
could be upgraded with a single-crystal digestion to yield (R)-
genation catalyst for the preparation of 2 together with initial
investigations into process optimisation.
Results and Discussion
2
-methylsuccinamic acid in >99.5% ee containing less than 1
The hydrogenation substrate, 2-methylenesuccinamic acid
ppm rhodium.
(2), was obtained by treatment of itaconic anhydride with
aqueous ammonium hydroxide followed by neutralization
of excess base with dilute hydrochloric acid (Scheme 1).5
Analysis of the substrate thus obtained indicated a retention
of chloride of approximately 1 wt %. Replacement of
hydrochloric acid by sulfuric acid produced a chloride-free
product. As will be described below, the presence or absence
of this chloride-containing impurity was found to have a
dramatic effect on the overall reaction rates obtainable.
Having chosen a set of standard conditions that we have
found to be routinely applicable for early-stage catalyst
Introduction
Both enantiomers of 2-methylsuccinamic acid (2) are
important chiral building blocks for the synthesis of numer-
ous biologically active compounds.1 A synthetic approach
to enantiomerically enriched 2 via asymmetric hydrogenation
of 2-methylenesuccinamic acid (Scheme 1) has potentially
the combined advantages of high selectivity, high efficiency,
and the availability of both enantiomers by using opposite
enantiomers of the chosen catalyst. Such an approach has
been previously reported, albeit with moderate enantiose-
lectivities, high catalyst loadings, and long reaction times
,2
2
screening (18 h at 60 psi H , 0.2 M solution of substrate in
MeOH, room temperature, and S/C of 100), the hydrogena-
tion study commenced with an initial screen of several
3
,4
[
(diphosphine)Rh(COD)]BF
4
precatalysts containing the
(75-77% ee with a molar substrate-to-catalyst ratio (S/C)
6
-8
diphosphines shown in Figure 1.
All reactions gave
5
of 100 to 1000 over 20 h). Herein we report a study
performed to identify a more efficient asymmetric hydro-
complete conversion, and the resulting enantioselectivities
are represented in Figure 2. Interestingly, under these
conditions, the presence of the chloride-containing impurity
had no overall effect on the general trend observed for
enantioselectivity.
*
Author for correspondence. E-mail: ccobley@dow.com.
(1) For an example of the use of (R)-2-methylsuccinamic acid, see: (a) Ikeura,
Y.; Doi, T.; Fujishima, A.; Natsugari, H. Chem. Commun. 1998, 2141-
2
142. (b) Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.;
With these initial results in hand, four precatalysts were
identified as candidates worthy of further examination,
Fujishima, A.; Tanaka, T.; Kasahara, F.; Kawada, M.; Natsugari, H. J. Med.
Chem. 1999, 42, 3982-3993.
2) For an example of the use of (S)-2-methylsuccinamic acid, see: Fuji, T.;
Ogawa, N. Tetrahedron Lett. 1972, 13, 3075-3078.
3) (a) Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.; Wiley-
Interscience: New York, 1994. (b) ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 1. (c) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: New York, 2000.
(
(6) 5-Fc ) 1, 1′-bis(2,5-dialkylphospholano)ferrocene
(7) COD ) 1,5-cyclooctadiene
(
(8) (a) Burk, M. J.; Gross, M. F. Tetrahedron Lett. 1994, 35, 9363-9666. (b)
Berens, U.; Burk, M. J.; Gerlach, A.; Hems, W. Angew. Chem., Int. Ed.
2000, 39, 1981. (c) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.;
Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207-6208. (d)
Burk, M. J. Acc. Chem. Res. 2000, 33, 363-372 and references therein; (e)
Henschke, J. P.; Burk, M. J.; Malan, C. J.; Herzberg, D.; Peterson, J. A.;
Wildsmith, A. J.; Cobley, C. J.; Casy, G. AdV. Synth. Catal. 2003, 345,
300-307.
(
4) For industrial examples of asymmetric hydrogenation, see: Blaser, H. U.;
Spindler, F.; Studer, M. Appl. Catal. A: Gen. 2001, 221, 119-143.
5) Takeda, H.; Tachinami, T.; Hosokawa, S.; Aburatani, M.; Inoguchi, K.;
Achiwa, K. Chem. Pharm. Bull. 1991, 39, 2706-2708.
(
1
0.1021/op0256183 CCC: $25.00 © 2003 American Chemical Society
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
407
Published on Web 04/11/2003

Figure 1. Diphosphines screened for the asymmetric hydrogenation of 2-methylenesuccinamic acid.
Table 1. Effect of reduced precatalyst loadings
conv. ee
a
b
entry
precatalyst
S/C (%)
(%)
1
[(R,R)-Me-DuPHOS Rh COD]BF
[(R,R)-Me-DuPHOS Rh COD]BF
4
4
100 >98 94 (S)
1000 >98 87 (S)
100 >98 95 (R)
1000 >98 94 (R)
100 >98 93 (R)
1000 >98 87 (R)
100 >98 91 (S)
2
3
4
5
6
7
8
[(S,S)-Et-DuPHOS Rh COD]BF
[(S,S)-Et-DuPHOS Rh COD]BF
4
4
[(S,S)-Et-FerroTANE Rh COD]BF
[(S,S)-Et-FerroTANE Rh COD]BF
[(S,S)-i-Pr-FerroTANE Rh COD]BF
4
4
Figure 2. Enantioselectivities obtained with a series of rhodium-
based catalysts.
4
[(S,S)-i-Pr-FerroTANE Rh COD]BF4 1000 >98 83 (S)
namely [(R,R)-Me-DuPHOS Rh COD]BF
OS Rh COD]BF , [(S,S)-Et-FerroTANE Rh COD]BF
(S,S)-i-Pr-FerroTANE Rh COD]BF . The next phase in the
4
, [(S,S)-Et-DuPH-
a
1
6
Determined by H NMR on the crude reaction mixture (d -DMSO).
9
b
Determined by chiral GC on the methyl ester derivative.
4
4
, and
[
4
investigation was to determine the effect on enantioselectivity
when reducing the catalyst loading to S/C ) 1000 for each
promising precatalyst (Table 1). At this stage of the project,
only the chloride-containing substrate was available and this
was used in subsequent small-scale development work. All
reactions were performed overnight, and although complete
conversion was achieved in each case, the (S,S)-Et-DuPHOS-
containing rhodium catalyst was the only candidate to retain
a high level of enantioselectivity (94% ee).
that higher pressures have a positive effect (cf. entries 2 and
, Table 2). In order not to discard at this early development
stage an electronically and structurally different catalyst,
4
8
b
[
(S,S)-Et-FerroTANE Rh COD]BF
4
was also included in
this brief study of the effect of temperature and pressure.
Although this complex resulted in a more active catalyst than
4
[(S,S)-Et-DuPHOS Rh COD]BF (cf. reaction times for
entries 2 and 6, and entries 5 and 8, Table 2), variations in
both temperature and pressure did not improve the enantio-
selectivity (entries 6-8, Table 2).
Further studies revealed that the hydrogenation with
4
[(S,S)-Et-DuPHOS Rh COD]BF remained highly enantio-
2-Methylenesuccinamic acid has low solubility in MeOH;
selective under a variety of conditions (Table 2). As expected,
an increase in temperature or pressure or both resulted in a
faster reaction, but the reaction was found to be very slow
at lower temperatures (entry 1, Table 2). It is debatable if
variations in pressure or temperature could offer any marked
improvement on enantioselectivity, but it may be possible
therefore, the effect of adding triethylamine to aid dissolution
was investigated together with variations in concentration.
It is evident from the results shown in Table 3, that the
addition of triethylamine increased the rate of the reaction,
but at the expense of selectivity. The observed increase in
408
•
Vol. 7, No. 3, 2003 / Organic Process Research & Development

Table 2. Effect of pressure and temperature
a
b
c
entry
precatalyst
temp (°C)
H
2
pressure (psi)
time (min)
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
[(S,S)-Et-DuPHOS Rh COD]BF
4
0
20
45
20
45
20
20
45
60
60
60
140
140
60
140
140
>18 h
240
140
120
90
120
45
33
>98
>98
>98
>98
>98
>98
>98
93 (R)
94 (R)
96 (R)
97 (R)
95 (R)
87 (R)
72 (R)
86 (R)
“
“
“
“
[(S,S)-Et-FerroTANE Rh COD]BF
“
“
4
20
a
Maximum time within which the reaction was complete. b Determined by H NMR on the crude reaction mixture (d
1
-DMSO). c Determined by chiral GC on the
6
methyl ester derivative.9
Table 3. Effect of substrate concentration and addition of
triethylamine
Table 4. Solvent screen for the asymmetric hydrogenation of
2-methylenesuccinamic acid
H
2
pressure concentration timea
conv.b eec
conv. (%)a
ee (%)b
entry
(psi)
(M)
(h) additive (%)
(%)
entry
solvent
1
2
3
4
5
6
7
8
60
60
60
0.3
0.3
1.0
1.0
0.3
0.3
1.0
1.0
4
-
>98 94 (R)
>98 74 (R)
>98 94 (R)
>98 69 (R)
>98 97 (R)
>98 72 (R)
>98 97 (R)
>98 68 (R)
1
2
3
4
5
6
7
8
MeOH
EtOH
i-PrOH
>98
37
87
5
24
21
2
97 (R)
84 (R)
97 (R)
-
2.5 NEt
3
3
3
3
<10
-
60
5
2
2
NEt
-
CF CH OH
3
2
140
140
140
140
THF
EtOAc
17 (S)
c
NEt
-
<8
5
CH Cl2
-
c
2
NEt
acetone
9
9
10
toluene
R,R,R-trifluorotoluene
0
0
-
a
b
-
Maximum time within which the reaction was complete. Determined by
1
-DMSO). c Determined by chiral GC
H NMR on the crude reaction mixture (d
on the methyl ester derivative.
6
9
a
Determined by 1H NMR on the crude reaction mixture (d
6
9 c
-DMSO).
Unable to obtain
b
Determined by chiral GC on the methyl ester derivative.
due to coeluting impurity.
activity may be due to triethylamine either reducing the
detrimental effect that the chloride containing contaminant
has on the reaction (see below for further discussions) or by
simply aiding dissolution of the substrate. It may also be
argued that the observed decrease in enantioselectivity is due
to carboxylate formation, which competes with the amide
carbonyl as the metal binding site.10 Although the reaction
was somewhat slower when run as a slurry (1.0 M without
Table 5. Effects of reducing the substrate-to-catalyst ratio
substrate
input (g)
timea
(min)
conv.
(%)b
ee
entry
S/C
(%)c
3
NEt , entry 7, Table 3), the enantioselectivity remained
1d
2
3
4
5
6
7
1000
1000
5000
10000
20000
50000
100000
15 g
15 g
15 g
15 g
15 g
40 g
40 g
117
4
24
>98
>98
>98
>98
>98
>98
>98
97 (R)
96 (R)
97 (R)
96 (R)
97 (R)
97 (R)
96 (R)
unaffected, hence making this procedure preferable.
A study of alternative solvents confirmed MeOH to be
the solvent of choice (Table 4). The same level of enantio-
selectivity was obtained in i-PrOH but with a concomitant
decrease in the reaction rate as shown by the lower
conversion.
46
102
242
447
Having broadly identified favourable reaction conditions,
a direct comparison between the chloride-containing and the
a
b
Maximum time within which the reaction was complete. Determined by
1
-DMSO). c Determined by chiral GC
Reaction performed with substrate batch
H NMR on the crude reaction mixture (d
6
9
d
on the methyl ester derivative.
(
9) To assign the enantiomer elution order, a reaction mixture corresponding
containing 1% chloride impurity.
20
to 92% ee was recrystallised from MeOH {[R]
D
) +18.2 (c 2.0, MeOH)}.
By comparison to a literature value for (S)-2-methylsuccinamic acid
[R]22
) -17.7 (c 2.0, MeOH)}, the major product for this reaction was
5
{
D
chloride-free substrates was made (entries 1 and 2, Table
5). It was at this stage that the dramatic effect of the chloride
contaminant on reaction rates was realized. The turnover
assigned as (R)-2-methylsuccinamic acid. This corresponds to the first eluting
enantiomer in the GC method used.
(
10) (a) Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew. Chem.,
Int. Ed. 1998, 37, 1931-1933. (b) Burk, M. J.; Bienewald, F.; Challenger,
S.; Derrick, A.; Ramsden, J. A. J. Org. Chem. 1999, 64, 3290-3298.
-
1
frequency increased from 500 h to an average of over
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
409

-1
1
3000 h , the reaction being 26 times faster for the chloride-
Experimental Section
free substrate, with the enantioselectivity being unaffected.
Interestingly, when the chloride-free substrate was hydro-
genated under the same conditions and using a precatalyst
General Methods. Unless otherwise stated, all chemicals
and reagents were purchased from commercial sources and
used without further purification. Ammonium hydroxide,
28% aqueous solution, and itaconic anhydride were pur-
chased from Aldrich and 4 M sulfuric acid from Fisher
Scientific. Standard HPLC grade MeOH, purchased from
Fisher Scientfic, was used throughout the hydrogenation
studies. Standard HPLC grade i-PrOH, purchased from Fisher
Scientific, was used for the crystal digestions.
2
prepared from [RhCl(COD)] and 2 equiv of (R,R)-Et-
DuPHOS at S/C ) 1000, the reaction took 31 min to go to
-
1
completion (turnover frequency ≈ 2000 h ) with 97% ee,
supporting the hypothesis that the lower reaction rates are
due to the presence of chloride ions. With this information
in hand, the substrate-to-catalyst ratio was systematically
reduced with the chloride-free material to explore the process
limitations (entries 2-7, Table 5). Ultimately, the high
activity of this catalyst for the asymmetric hydrogenation of
this substrate was demonstrated by performing the reaction
at the extremely low catalyst loading of S/C ) 100000 (entry
1
13
Analytical Methods. H and C NMR were recorded on
a Bruker WH-400 spectrometer. Spectra were recorded in
d -DMSO at ambient temperature. Chloride content was
6
analysed via titration with silver nitrate. Rhodium content
was determined for the Rh-104 isotope using neutron
activation. GC analysis was performed on a Perkin-Elmer
Autosystem XL equipped with a FID detector. Enantiose-
lectivity determinations for the hydrogenation reactions were
performed on the methyl ester of 2-methylsuccinamic acid12
by derivatisation of a sample with trifluoroacetic anhydride
and MeOH (Varian Chirasil Dex CB column, 25 m × 0.25
mm, 0.25 µm). A temperature program of 105 °C for 5 min,
then 5 °C/min to 150 °C was used with carrier gas helium
at 20 psi (retention times 12.74 min for the (R) enantiomer
and 12.85 min for the (S) enantiomer).
Preparation of 2-Methylenesuccinamic Acid. To a 1-L
round-bottomed flask equipped with a mechanical stirrer was
4
loaded 28% NH OH in water (154 g, 1.2 mol). After cooling
the solution to 0 °C, itaconic anhydride (98.0 g, 0.87 mol)
was added slowly, keeping the reaction temperature below
7, Table 5).
A sample of the crude product was purified by crystal
digestion in i-PrOH (50 wt %) at 40 °C, cooling to -5 °C,
filtering, and drying in vacuo (20 °C). This gave the desired
(
(
R)-2-methylsuccinamic acid as an off-white, crystalline solid
77% recovery) in >99.5% ee.
When using homogeneous catalysis for the manufacture
of active pharmaceutical ingredients, the presence of residual
metal in the final product is of great concern. Current
guidelines from The European Agency for the Evaluation
11
of Medicinal Products suggest that concentration levels for
the platinum group metals should be less than 5 ppm for
orally delivered pharmaceuticals. In light of this, rhodium
content analyses of both the crude and the upgraded material
from the reaction performed at S/C 100000 were carried out,
giving 9.0 ( 0.4 and 0.88 ( 0.05 ppm, respectively.
Furthermore, analysis of both crude and upgraded material
from the reaction performed at S/C 20000 showed that the
rhodium content could be decreased from 36 ( 1 to 9.8 (
5
°C. When the addition of the anhydride was complete, the
mixture was allowed to warm to room temperature. After
stirring for 2 h the reaction was cooled to 0 °C. The pH of
the reaction mixture was adjusted to below 1 by dropwise
addition of 4 M H SO (250 mL) and then left to stir at room
2 4
temperature for 18 h. The slurry was cooled to 0 °C before
0.4 ppm with a single crystal digestion. This demonstrates
that the recommended rhodium concentration levels can be
achieved using standard processing techniques.
filtration through a sintered glass frit. The wet cake was
washed with 100 mL of dilute H
was dried at room temperature in a vacuum oven to yield
0 g of crude 2-methylenesuccinamic acid which contained
2 4
SO (pH < 3). The solid
Conclusions
7
1
In conclusion, an initial screen to identify a suitable
precatalyst and subsequent investigations into the effects of
various process parameters determined an extremely efficient
route to highly enantiomerically enriched (R)-2-methylsuc-
cinamic acid via asymmetric hydrogenation with [(S,S)-Et-
13 mol % of the undesired 3-methylenesuccinamic acid ( H
NMR). Crystal digestion in ethanol (120 mL) yielded 59.2
g of the desired 2-methylenesuccinamic acid (53% yield),
5
mp 137-138 °C (lit. mp 150-152 °C for material prepared
with HCl).
When 2-methylenesuccinamic acid was prepared using
DuPHOS Rh COD]BF
crucial in obtaining extremely low catalyst loadings. Elimi-
nating trace amounts of chloride contaminant by using H
SO in place of HCl during substrate preparation enabled us
4
. Substrate purity was found to be
5
hydrochloric acid, as described in the literature, the material
obtained was found to contain 1% chloride by weight.
General Hydrogenation Procedure. Unless stated oth-
erwise, all reactions were carried out in either a 50-mL Parr
microreactor or a Baskerville multiwell reactor, both modi-
fied with an injection port allowing introduction of solutions
via syringe. The reactors were used with a suitable glass liner
and a magnetic stirrer. All solvents were deoxygenated prior
to use by sparging with nitrogen for 1 h.
2
-
4
to achieve complete conversion to (R)-2-methylsuccinamic
acid in 96% ee with S/C 100000:1 (w/w ≈ 21400, reaction
-
1
time 7.5 h, TOF ≈ 13000 h ). Purification of the crude
reaction product by crystal digestion in i-PrOH enabled (R)-
2-methylsuccinamic acid to be obtained in >99.5% ee with
less than 1 ppm rhodium content.
(
12) 2-Methylsuccinamic acid methyl ester: 1H NMR (400 MHz, d
6
-DMSO) δ
3
(11) See draft guidelines from the European Agency for the Evaluation of
ppm 7.35 (1H, NH, br s), 6.83 (1H, NH, br s), 3.61 (3H, CH
O, s), 2.79
Medicinal Products, 27 June 2002, http://www.emea.eu.int/pdfs/human/swp/
(1H, CHCH
(1H, CHHC(O)NH
3
m), 2.45 (1H, CHHC(O)NH
2
, dd, J ) 7.3 and 15.3), 2.21
4
44600en.pdf
Vol. 7, No. 3, 2003 / Organic Process Research & Development
2
, dd, J ) 7.3 and 15.3), and 1.10 (3H, CH
3
, d, J ) 7.0).
410
•

Typical Screen Experiment. A glass liner was charged
with 2-methylenesuccinamic acid (387 mg, 3 mmol), pre-
catalyst (0.03 mmol), and a cross-shaped magnetic stirrer
bar. The liner was placed in a 50-mL Parr pressure vessel
and the reactor assembled and flushed three times with
nitrogen (100 psi). MeOH (10 mL) was added through the
septum of the reactor via syringe. The reactor was purged
again with nitrogen (three pressurization/release cycles to
vessel was then charged with hydrogen (140 psi). The
temperature was maintained at 45 °C throughout the course
of the reaction and the hydrogen pressure readjusted to 140
psi after every 4 psi of hydrogen consumed. After no further
hydrogen uptake was observed, the vessel was cooled to
room temperature, the hydrogen pressure released, and the
system flushed once with nitrogen (140 psi) prior to vessel
disassembly. The reaction mixture was transferred to a 1-L
round-bottomed flask and concentrated under reduced pres-
sure to yield the crude reaction product as an off-white solid
100 psi). The reactor was finally pressurized to 60 psi with
hydrogen and stirred at room temperature overnight. The
1
hydrogen was then released and a sample submitted for ee
(38.7 g, 95.3% crude yield). H NMR spectroscopy and chiral
GC were used to analyse conversion and enantioselectivity
respectively (>98% conv., 96.4% ee).
1
analysis. Conversion was determined by H NMR (d
6
-
-
1
DMSO). 2-Methylsuccinamic acid: H NMR (400 MHz, d
6
DMSO) δ ppm 7.32 (1H, NH, br s), 6.79 (1H, NH, br s),
.67 (1H, CHCH m), 2.40 (1H, CHHC(O)NH , dd, J 7.3
and 15.3), 2.10 (1H, CHHC(O)NH , dd, J 7.3 and 15.3), and
, d, J 7.0). C NMR (100 MHz, d -DMSO) δ
ppm 177.7, 173.3, 38.7, 36.1, and 17.3.
Larger-Scale Hydrogenation. The reaction was carried
out in a 600-mL pressure vessel equipped with a mechanical
stirrer, a cooling/heating coil, an injection port, a temperature
probe, and a pressure transducer and fitted with a glass liner.
Crystal Digestion of 2-Methylsuccinamic Acid. A 100-
mL, three-neck, round-bottomed flask fitted with a reflux
condenser and a mechanical stirrer was loaded with crude
(R)-2-methylsuccinamic acid (27.0 g, 98.0% ee, 5% methyl
ester) and i-PrOH (24.8 g). The resulting slurry was heated
to 40 °C and stirred at that temperature for 1 h. This slurry
was cooled to -5 °C over 2 h and filtered. The resulting
wet cake was washed with cold 1:1 (v/v) i-PrOH/toluene
and dried in vacuo (20 °C) to a constant weight. The final
off-white solid (20.8 g, 76.8% recovery) was >99.5% ee by
chiral GC analysis (derivatized as the methyl ester). Mp
2
3
2
2
13
1.06 (3H, CH
3
6
2-Methylenesuccinamic acid (40.0 g, 0.31 mol) was added
to the glass liner, followed by MeOH (306 mL). The vessel
was assembled and pressurized to 140 psi with nitrogen. The
reaction was stirred at the maximum rate (∼750 rpm, stirrer
assembly consists of two propellers, one positioned just
below the solvent surface and one near the bottom of the
solution) for 30 min during which time the temperature was
maintained at 45 °C (internal). The pressure was then
released. To ensure that an oxygen-free atmosphere was
attained, the vessel was recharged with nitrogen (140 psi)
and vented after stirring for 10 min. This was repeated three
times. The vessel was subsequently charged and vented three
times with hydrogen (140 psi). [(S,S)-Et-DuPHOS Rh(COD)]-
13
131-132 °C [lit. mp for (S)-2-methylsuccinamic acid 132-
133.5 °C].
Acknowledgment
We thank Natasha Chesseman (chiral GC) from the Dow-
Chirotech analytical team and Larry Nicholson (chiral GC),
Bruce Bell (GC-MS), Sam Qiu (NMR), and Ward Rigot
(Neutron Activation) from the Dow analytical team for their
skilled technical assistance.
Received for review December 17, 2002.
OP0256183
4
BF (3.7 mg, 0.0031 mmol, molar S/C 100000) was then
added as a MeOH solution (5 mL, prepared under nitrogen
using deoxygenated anhydrous solvent) via syringe. The
(13) Adams, R.; Fles, D. J. Am. Chem. Soc. 1959, 81, 4946-4951.
Vol. 7, No. 3, 2003 / Organic Process Research & Development
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