Highly enantioselective hydrogenation of itaconic acid derivatives with a chiral bisphospholane-Rh(I) catalyst

Article abstract of DOI:10.1002/adsc.200404080

The new - commercially in multi-kg quantities available - chiral bisphospholane ligand, catA-Sium M, has been successfully used in the Rh(I)-catalysed enantioselective hydrogenation of itaconic acid derivatives. Chiral β-substituted succinic acid derivati

Full text of DOI:10.1002/adsc.200404080

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Highly Enantioselective Hydrogenation of Itaconic Acid
Derivatives with a Chiral Bisphospholane-Rh(I) Catalyst
Juan Almena,a,* Axel Monsees,a Renat Kadyrov,a Thomas H. Riermeier,a
Battsengel Gotov,b Jens Holz,c Armin Börnerc , d,*
a
Degussa AG, Degussa Homogeneous Catalysts, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany
Fax: (þ49)-6181-592-417, e-mail: juan.almena@degussa.com
b
Degussa AG, Project House Catalysis, Industriepark Höchst G 830, 65926 Frankfurt/Main, Germany
c
Leibniz-Institut für Organische Katalyse an der Universität Rostock e.V., Buchbinderstr. 5/6, 18055 Rostock, Germany
Fachbereich Chemie der Universität Rostock, A.-Einstein-Str. 3a, 18059 Rostock, Germany
d
E-mail: armin.boerner@ifok.uni-rostock.de
Received: March 12, 2004; Accepted: August 12, 2004
Abstract: The new – commercially in multi-kg quan-
tities available – chiral bisphospholane ligand, catA-
Siumꢀ M, has been successfully used in the Rh(I)-
catalysed enantioselective hydrogenation of itaconic
acid derivatives. Chiral ß-substituted succinic acid
derivatives were produced in good to excellent enan-
tioselectivities. Turnover frequencies by up to
40,000 hÀ1 have been achieved.
of precious benzene-1,2-diphosphane as starting materi-
al.
Recently, we have developed a facile access to the new
chiral phospholane ligand 1, called catASiumꢀ M.[11,12]
First applications in the enantioselective preparation
of chiral b-amino acid derivatives showed the high cata-
lytic potential of Rh complexes based on catASiumꢀ M.
Keywords: asymmetric catalysis; chiral bisphospho-
lanes; enantioselective hydrogenation; homogeneous
catalysis; P ligands; rhodium
The increasing use of chiral building blocks in pharma-
Interestingly, in several cases the Rh catalyst of the
ceuticals, agrochemicals, flavours, and fragrances has new phospholane showed superior catalytic properties
rendered the enantioselective synthesis of chiral com- in comparison to a related DUPHOS complex. Prompt-
pounds on an industrial scale an important topic.[1] Since ed by these promising results we envisaged the hydroge-
the seminal work in 1968 by Knowles[2a] and Horner[2b] nation of other substrates. We were particularly interest-
on the application of chiral phosphane ligands for the ed in the preparation of enantiomerically pure b-substi-
Rh-catalysed enantioselective reduction and the first in- tuted succinic acids by hydrogenation of corresponding
dustrial application to the synthesis of l-DOPA,[3] liter- itaconic acid derivatives. The products are chiral bifunc-
ally more than hundreds of chiral trivalent phosphorus- tional C5-building blocks which are important inter-
containing ligands have been synthesised and tested in mediates for the preparation of natural products and
the metal-catalysed homogeneous hydrogenation of pharmaceuticals.[13] Here we present our results on the
functionalised and non-functionalised olefins, ketones, enantioselective synthesis of succinic acid derivatives
imines and other prochiral substrates.[4] Diphosphanes by employment of Rh complexes of catASiumꢀ M.
like DIOP,[5] DIPAMP,[6] BINAP,[7] JOSIPHOS[8] and
First studies on the hydrogenation of dimethyl itaco-
DUPHOS[9] representing so-called privileged ligands nate (2a) were performed under isobaricconditions at
have found several applications in the industrial produc- a hydrogen pressure of 4 bar (Table 1). In order to eluci-
tion of chiral intermediates.[10] In particular, the chiral date the effect of the type of the catalyst preparation on
bisphospholane DUPHOS and its derivatives turned the hydrogenation we employed the in situ prepared
out to be one of the most powerful ligands, apparently precatalyst and the isolated precatalyst, respectively.
due to the proximity of the chiral information to the cat- When an in situ generated precatalyst was used, the chi-
alytically active centre in relevant Rh complexes and the ral ligand 1 and Rh(COD)2BF4 were stirred at room
high basicity of the ligating phosphorus atoms. Unfortu- temperature for 20 minutes before the addition of the
nately, from the syntheticpoint of view, the synthesis of
substrate occurred. In the subsequent hydrogenation di-
DUPHOS seems to be rather expensive, due to the use methyl itaconate was reduced in methanol in 96% ee
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DOI: 10.1002/adsc.200404080
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(entry 1). This value could be improved to 98% ee when worthy of note that under the same reaction conditions
the reaction was carried out in dichloromethane as sol- in a parallel experiment Me-DUPHOS only gave 10%
vent (entry 2). The enantioselectivity of our catalyst ee.[14]
proved to be similar to that achieved with an Me-DU-
For the reduction of b-substituted itaconic acid deriv-
PHOS catalyst, which gave in our hand 97% ee. A fur- atives only a few systems are known which provide sat-
ther improvement of the ee was achieved by using the isfactory enantioselectivities.[15] Substrates 2d,e were
isolated Rh precatalyst (99% ee, entry 3). In this case easily prepared from dimethyl succinate and benzalde-
the isolated Rh complex was dissolved prior to the addi- hyde and isobutyraldehyde, respectively, via Stobbe
tion of the substrate. Finally under optimal reaction con- condensation.[16] The obtained E/Z-isomericmixtures
ditions dimethyl itaconate could be completely reduced of the substrates were subjected to the hydrogenation
at a TON 10,000 within fifteen minutes with an enantio- procedure. Results are listed in Table 2. 2-Benzylidene-
meric excess of 99% (entry 4). In order to achieve such succinic acid 1-methyl ester (2d) was hydrogenated with
high turnover frequencies it was necessary to use a high- an in situ generated precatalyst of catASiumꢀ M in
er pressure (8 bar). It is worthy of mention that the methanol with 86% ee (entry 1). When dichlorome-
elevated pressure did not affect the ee.
thane was used as solvent the enantioselectivity could
Not only could dimethyl itaconate (2a) be reduced in be improved to 98% (entry 2). Similar results were not-
excellent enantioselectivities, but also itaconic acid (2b) ed on application of substrate 2e. In methanol good
was hydrogenated with 97% ee. Addition of a base enantioselectivities were obtained (91% ee, entry 3).
slightly increased the enantioselectivity to 98% (en- By application of acetone as solvent still higher enantio-
try 6). Another interesting substrate is the mono-ester selectivities could be achieved (95% ee, entry 4). When
2c. The product of the hydrogenation, (R)-2-methylsuc- the precatalyst was isolated prior to the hydrogenation,
cinic acid 4-methyl ester, represents a valuable building dichloromethane was found to be the solvent of choice
block because of the different reactivities of both car- (94% ee, entry 5). The presence of one equivalent of
[13]
boxylicgroups.
High enantioselectivities were ob- an amine further increased the enantioselectivity to
tained in the hydrogenation of this substrate both in 96% (entry 6). In general enantioselectivities registered
methanol and dichloromethane (entries 7–9). Using are comparable with those obtained with the related Rh-
the same precatalyst and by modifying the reaction con- Me-DUPHOS catalyst which gave under the same reac-
ditions, it was found that our catASiumꢀ M in dichloro- tion conditions in our hands 96% ee.
methane at S/C 1,000 and at an initial pressure of 8 bar
In conclusion, a rhodium(I) catalyst based on the new
catalysed the reduction of substrates 2 in 98% ee. It is chiral bisphospholane ligand 1 (catASiumꢀ M) repre-
Table 1. Hydrogenation of non-substituted itaconates 2a–c.[a]
Entry
Substrate
Type of precatalyst
Solvent
TON
ee [%]
1
2
2a
2a
2a
2a
2b
2b[e]
2c
prepared in situ
prepared in situ
Isolated
Isolated
Isolated
Isolated
Isolated
Isolated
Isolated
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
MeOH
MeOH
CH2Cl2
CH2Cl2
400
500
96
98
99
99
97
98
98
98
99
3
500
[c]
4[b]
5
10,000[d]
500
6
500
400
7
8[b]
9
2c
2c
1,000
4,000[f]
[a]
Unless indicated otherwise, the substrate concentration was 0.5 M. Unless indicated otherwise, all the reactions were run at
4 bar hydrogen for 3 h at 258C.
[b]
[c]
[d]
[e]
[f]
The experiment was performed at 8 bar initial hydrogen pressure.
The substrate concentration was 1 M.
An average TOF of 40,000 hÀ1 was calculated.
One equivalent of i-Pr2NEt was added.
TOF¼8,000 hÀ1
.
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Enantioselective Hydrogenation of Itaconic Acid Derivatives
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Table 2. Hydrogenation of b-substituted itaconic acid deriva-
tives 2d, e.[a]
umn (250 mmꢀ4.6 mm) and detection by a diode array UV/
Vis detector at 214 nm. For compounds 2a,b,e: n-hexane/2-
propanol 95/5; 1.25 mL/min; 2b, e were converted into their di-
methyl esters with TMSCl in methanol prior to the analysis. For
compound 2c: n-hexane/2-propanol, 90/10; 1.25 mL/min. For
compound 2d: n-hexane/2-propanol, 90/10; 1 mL/min; 2d was
converted into its dimethyl ester with TMSCl in methanol prior
to the analysis. The values of turnover numbers and ee corre-
spond to the average value of at least 2 experiments.
Entry Substrate Type of precatalyst Solvent TON ee [%]
1
2
3
4
5
6
7
2d
2d
2e
2e
2e
prepared in situ
prepared in situ
prepared in situ
prepared in situ
Isolated
MeOH 500 86
CH2Cl2 500 98
MeOH 192 91
Acetone 186 95
MeOH 196 90
CH2Cl2 196 94
CH2Cl2 200 96
Typical Procedure for the Asymmetric
Hydrogenations (Table 1, entry 4)
In an argon atmosphere, 0.1 mL of a 0.01 M solution of ligand 1
in methanol (0.001 mmol, 0.6 mg) was added to 0.1 mL of a
0.01 M solution of Rh(COD)2BF4 in methanol (0.001 mmol,
0.4 mg) and the resulting mixture was stirred at room temper-
ature for 20 minutes. The precatalyst was transferred into a 50-
mL Parr autoclave with a magnetic stirrer and then 10 mL of a
0.5 M solution of substrate 3a in methanol (5 mmol, 0.8 g) were
added. The autoclave was closed, purged with hydrogen and
then pressurised with hydrogen to 4 bar. The reaction mixture
was stirred at 258C for 3 h (the pressure was maintained
around 4 bar by adding more hydrogen during the reaction).
After 3 h the hydrogen was released and the reaction mixture
was analysed by HPLC (0.5 mL was concentrated in vacuum;
the residue was taken up into 0.5 mL i-PrOH and 0.5 mL n-
hexane and filtered through a small plug of silica gel).
2e
Isolated
Isolated
2e[b]
[a]
Unless indicated otherwise, the substrate concentration
was 0.5 M. Unless indicated otherwise, all the reactions
were run at 4 bar hydrogen for 5 h at 258C.
[b]
One equivalent of i-Pr2NEt was added.
sents one of the most effective and enantioselective cat-
alysts for the hydrogenation of non-substituted and b-
substituted itaconic acid derivatives known up to now.
The reported results show that our new ligand catASi-
umꢀ M (1) displays higher performance in several reac-
tions compared to the Me-DUPHOS ligand. The excel-
lent enantioselectivities observed (up to 99%), the high
catalytic activity (TOF up to 40,000 hÀ1) and the availa-
bility of this ligand on a multi-kg scale makes it suitable
for extensive industrial applications.[17] The synthesis of
other members of this new ligand family as well as stud-
ies on syntheticapplications in other reactions and their
application in pilot plant processes are in progress.
Typical Procedure for the Esterification of
Hydrogenation Products with TMSCl
After evaporating the reaction solvents, the residues were tak-
en up in 0.5 mL of a freshly prepared 2 M solution of trimethyl-
silyl chloride (TMSCl) in methanol and stirred at room temper-
ature for 1 h. The solvents were evaporated (caution, evolution
of HCl) and the residues were taken up in 0.5 mL of 2.5 M
NaOH and extracted with t-butyl methyl ether (MTBE). The
organicphase was separated and dried with Na SO4. After
2
the solvent switch to i-PrOH/n-hexane the reaction mixtures
were analysed by HPLC.
Experimental Section
General Remarks
Acknowledgements
The precatalyst preparation and manipulation were performed
in a glove-box under a dry argon atmosphere. Solvents were re-
agent grade and dried and distilled before use following stand-
ard procedures. [Rh(COD)2]BF4 was purchased from Heraeus
and used as received. Dimethyl itaconate (2a) and itaconic acid
(2b) were purchased (Aldrich) and used without further puri-
fication. The following compounds were synthesised according
to literature procedures: 1,[11] [Rh(COD)1]BF4,[11], 2c,[16] 2d,e
(used as a mixture of Z and E isomers).[15] Products 3b,c were
derivatised into their dimethyl esters prior to the reaction mix-
tures analyses. The absolute configuration of the products 3a – c
was assigned by analogy, through HPLC elution order with an
enantiopure sample of dimethyl (R)-2-methylsuccinate. The
absolute configuration of the products 3d,e was assigned by
comparisons of the rotation signs with literature data. Enantio-
meric excesses were determined by HPLC: Chiralcel-OD col-
We are grateful for the financial support provided by the BMBF
and the Fonds der Chemische Industrie. We thank Dr. U. Dinger-
dissen and Prof. Dr. K.-H. Drauz for valuable discussions.
References and Notes
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Blaser, Chem. Commun. 2003, 293; d) H.-U. Blaser, E.
Schmidt, Asymmetric Catalysis on Industrial Scale, Wi-
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gussa owned ligand and catalysts used in asymmetric hy-
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thylphospholanyl)maleicanhydride] is a member of this
family and it was previously known as MalPHOS, see
Ref.[11]
[6] B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L.
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[14] For this type of substrates the extremely poor catalysis
properties of members of the DUPHOS family are well
known, see: I. C Lennon, P. H. Moran, Chiral Catalysis
– asymmetric hydrogenation 2004, 22, 34.
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[16] A. R. Devi, S. Rajaram, Ind. J. Chem. 2000, 294.
[17] Samples of the rhodium complexes of catASiumꢀ M for
research can be obtained from Strem Chemicals. Gram
to multi-kg quantities can be obtained directly from De-
gussa AG.
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