Asymmetric synthesis of alkyl 5-oxotetrahydrofuran-2-carboxylates by
enantioselective hydrogenation of dialkyl 2-oxoglutarates over cinchona
modified Pt/Al O catalysts
2
3
a
a
b
a
ab
Katalin Balázsik, Kornél Szöri, Károly Felföldi, Béla Török and Mihály Bartók*
a
Organic Catalysis Research Group of the Hungarian Academy of Sciences and b Department of Organic Chemistry,
József Attila University, H-6720 Szeged, Dóm tér 8, Hungary. E-mail: bartok@chem.u-szeged.hu
Received (in Liverpool, UK) 12th January 2000, Accepted 22nd February 2000
Published on the Web 17th March 2000
The first direct asymmetric synthesis of chiral alkyl 5-oxo-
tetrahydrofuran-2-carboxylates (up to 96% ee), which are
important building blocks in the synthesis of natural
products by heterogeneous cinchona-modified Pt-catalyzed
hydrogenation of a-ketoglutaric acid esters and subsequent
cyclization of hydroxy esters is described.
also inefficient (24% ee).11 As a consequence, to the best of our
knowledge, no satisfactory enantioselective reduction of a-
ketoglutaric acid derivatives has been developed.
2 3
In this study two well known Pt/Al O reference catalysts
(Engelhard 4759, denoted E4759 and Johnson Matthey 94,
denoted JMC94) were used while the two modifiers [cinchoni-
dine (CD) and cinchonine (CN)] and 2-ketoglutaric acid were
all Fluka products. 9-Methoxy-10,11-dihydrocinchonidine
(MeOHCD) was kindly donated by Dr Martin Studer (Novartis,
Basel, Switzerland). The dimethyl and diethyl a-ketoglutaric
acid esters were prepared on the basis of a literature proce-
dure.10 The hydrogenations were performed in an atmospheric
batch reactor or in a Berghof Bar 45 autoclave at 20 °C as
described previously.2 After hydrogenation, the hydroxyester
obtained was subjected to a cyclization reaction with p-
The growing interest in the synthesis of important chiral
compounds provides significant impetus for asymmetric syn-
thesis. Owing to the recent environmental considerations and
safety concerns, the use of heterogeneous asymmetric methods
such as enantioselective hydrogenation are especially prefera-
1
ble. One of those, the cinchona alkaloid-modified platinum
,3
catalyst system, was found to be especially effective in the
1
2
hydrogenation of a-ketoesters and ketoacids and ketoacetals.
3
10
The most prominent substrates are ethyl pyruvate, pyr-
uvaldehyde dimethyl acetal, ketopantolactone and 1-ethyl-
,4-dimethylpirrolidine-2,3,5-trione, which can all be hydro-
genated with excellent enantioselectivity (91–98%) over
cinchona-modified Pt/Al catalysts.
toluenesulfonic acid according to the literature procedure.
2
4
During the reaction no racemization or inversion occured, as a
result the ee of the cyclic products corresponded to that of the
open chain hydroxy esters. Product identification was carried
5
4
1
2
O
3
out by GC–MS (HP5890 GC-HP5970 MSD) and H NMR
Here, we report a new successful enantioselective synthesis
of alkyl (R)-5-oxotetrahydrofuran-2-carboxylates, via the
asymmetric hydrogenation of a-ketoglutaric acid esters over
spectroscopy (Bruker AM500), while the enantiomeric excesses
{ee% (|[R] 2 [S]|) 3 100/([R] + [S])} were monitored by chiral
gas chromatography [HP 5890 GC-FID, 30 m long Cyclodex-B
(J&W Scientific) capillary column, carrier gas: He, 15 psi,
125 °C, retention time for (S)-isomer: 31.8 min, for (R)-isomer:
2 3
cinchona-modified Pt/Al O catalyst.
The target chiral esters are very frequently used synthons in
6
the synthesis of natural products. In addition, their utilization in
32.5 min]. The ee values were reproducible within 2%.
7
1–5
the free acid form as chiral derivatizing agents or as a template
According to earlier findings
two well known 5% Pt/
8
for acyclic stereoselection through asymmetric synthesis is
2 3
Al O references catalysts (E4759 and JMC94) were highly
also well known. The enantioselective hydrogenation of dialkyl
efficient in the enantioselective hydrogenation of activated a-
oxo-compounds. As a result, these samples were selected for the
enantioselective hydrogenation of diethyl a-ketoglutarate. Tak-
ing into account that in the literature, toluene and acetic acid
have mainly been applied as solvents in these systems, both of
them were tested first to find the most suitable medium, catalyst
and modifier for the hydrogenation. Although the enantiose-
lectivity in toluene is only moderate (up to 63% ee), using acetic
acid as solvent, the results are excellent (up to 93% ee) and
comparable or even slightly higher than those obtained with
2-ketoglutarates and the subsequent cyclization to alkyl 5-oxo-
tetrahydrofuran-2-carboxylates are shown in Scheme 1.
The existing process for the preparation of the target
compounds is a template synthesis based on the deamination of
enantiopure glutamic acid.9 Asymmetric pathways to their
perparation are enzymatic resolution of the racemic mixtures or
10
direct bioreduction of ketoglutaric acid esters. The former
process provides high enantiomeric excess, however, the yield
is obviously does not exceed 50% in the best case. The
bioreduction, however, is not an efficient method for the
preparation of enantiomers of high purity, since the ee values
ethyl pyruvate.1 As generally found, the ee was always
higher with the CD modifier than with the CN modifier. The
results obtained in the two solvents, including reaction rates and
optical yields, are tabulated in Table 1.
,2
12
(
up to 67%) vary considerably and significant decarboxylation
and byproduct formation may be observed. Heterogeneous
hydrogenation carried out on camphor-modified Raney Ni was
In the light of the results shown in Table 1 it can be concluded
that the JMC catalyst exhibited a slight but clear increase in both
reaction rates and optical yields (5–6% ee increase) compared to
E4759. It seems also clear that MeOHCD is the best modifier
for the reaction, the ee values obtained mostly exceed by ca.
1
0% those achieved with cinchonidine.
Since the enantioselective hydrogenation of a-ketoesters
over the Pt-cinchona catalyst system generally shows better
performance (higher reaction rates and optical yields) under
elevated hydrogen pressures, the effect of hydrogen pressure, on
1
the present system was also studied. According to the literature
a wide hydrogen pressure (1–100 bar) was studied with acetic
acid as solvent using the JMC94 catalyst and MeOHCD
modifier.
Scheme 1
DOI: 10.1039/b9000390p
Chem. Commun., 2000, 555–556
This journal is © The Royal Society of Chemistry 2000
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