The potential of membrane reactors in the asymmetric opening of meso-anhydrides

Article abstract of DOI:10.1016/S0040-4039(02)02075-0

A polymer attached cinchona-alkaloid was investigated in the asymmetric opening of meso-anhydrides. Variation of reaction parameters reduced the reaction time to 1 hour, which is very important for a continuous reaction. It turned out that due to product

Full text of DOI:10.1016/S0040-4039(02)02075-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8531–8533
The potential of membrane reactors in the asymmetric opening
of meso-anhydrides
Jens Wo¨ltinger,* Hans-Peter Krimmer and Karlheinz Drauz
Degussa AG, Business Unit Fine Chemicals, PO Box 1345, D-63403 Hanau, Germany
Received 5 April 2002; accepted 20 September 2002
Abstract—A polymer attached cinchona-alkaloid was investigated in the asymmetric opening of meso-anhydrides. Variation of
reaction parameters reduced the reaction time to 1 hour, which is very important for a continuous reaction. It turned out that due
to product inhibition of the catalyst the conversion and enantiomeric excess decreased rapidly during a continuous reaction. In
a repetitive batch system, it was possible to run the reaction over 18 cycles with a conversion of >99%. The ee value decreased
to 60% over the first 7 runs and was stable at this value for the last 11 runs. © 2002 Elsevier Science Ltd. All rights reserved.
meso-Anhydrides are versatile compounds for natural
product synthesis or for the preparation of active phar-
maceutical ingredients because of the potential for
desymmetrization.1 Both resulting functional groups
(ester and acid) can be transformed selectively, e.g. to
b-amino acids.2 A very encouraging approach to chiral
mono-esters is the ring opening catalyzed by chiral
amines. Cinchona alkaloids are the preferred catalysts
employed.3 This reaction suffers from very low reaction
temperatures, long reaction times and high catalyst
consumption in order to achieve high enantioselectivi-
ties.4 For an industrial application short reaction times
are essential to obtain a high space-time-yield and low
catalyst consumption is required for economical
reasons.
order to maintain the advantage of homogeneous cataly-
sis, a short reaction time is the key for a efficient
continuous process.
We chose cis-4-cyclohexene-1,2-dicarboxylic anhydride
1 as a model substrate (Scheme 1). The commercially
available (DHQD)2-AQN-ligand was employed as cata-
lyst: the reaction time was reduced from 60 h to 15 min
and the temperature could be raised from −20°C to
room temperature by using 100 mol% of catalyst and
10 equiv. of methanol. Under these conditions an enan-
tiomeric excess of 90% of 2 was obtained.
To synthesize a suitable polymer-attached catalyst we
started with the hydroxy-AQN-ligand 4 which was
synthesized according to a literature procedure.6 In
contrast to the polymer-attached AQN-ligand used in
the Sharpless-dihydroxylation, the AQN-ligand 4 was
attached to a linear polystyrene (Scheme 2). The
polystyrene 3 was prepared by radical polymerization
of styrene and p-chlorovinylstyrene in cyclohexane with
AIBN as radical initiator. The main reason for the
choice of this polymer is its good solubility in the
To run the reaction in a short reaction time and at
ambient temperature a high catalyst concentration
would be necessary. Therefore the ease and efficiency of
catalyst recycling is vital for the whole process.
Membrane reactors are the perfect set-up for reactions
which require high catalyst concentrations.5 Due to the
in situ recycling of catalysts the catalyst consumption
per kg product is decreased compared with a single
batch.
Besides a high retention of the polymer attached cata-
lyst, which has to be soluble in the reaction solvent in
Keywords: chemzyme-membrane-reactor; continuous reaction; repeti-
tive batch; asymmetric opening of anhydrides.
* Corresponding author. Tel.: +49-351-8314-2169; fax: +49-351-8314-
2255; e-mail: jens.woeltinger@degussa.com
Scheme 1. cis-4-Cyclohexene-1,2-dicarboxylic anhydride
was employed as a model substrate for the asymmetric open-
ing of meso-anhydrides.
1
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02075-0

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J. Wo¨ltinger et al. / Tetrahedron Letters 43 (2002) 8531–8533
Scheme 2. Preparation of the polymer-bound catalyst.
required solvent (toluene) and the ease of modification
of the chain length of the polymer in the radical
polymerization.
Using the polymer-attached catalyst 5 full conversion
was reached in 1 hour at room temperature. This is a
longer reaction time compared with the original
(DHQD)2-AQN ligand, where the reaction was com-
plete within 15 minutes under the same reaction condi-
tions, however the selectivity could be maintained. For
the continuous reaction we chose a reaction set-up,
which we adapted from our previous work (Scheme
3).5,7
Scheme 3. Reaction set-up for the continuous reaction. 30
min was selected as residence time. A 10 mL stainless steel
reactor was chosen together with a flow of 5 mL per pump.
The flow was controlled by mass flow meters (MFM). 0.25
mmol anhydride 1 in 5 mL toluene, 2.5 mM MeOH in 5 mL
toluene and 1.0 mmol catalyst 3 were set as concentrations.
In Fig. 1 the conversion and ee values of the continuous
reaction are illustrated. The intense decline of both ee
value and conversion is not caused by leaching of the
catalyst, even though the catalyst retention is poor at
95.4%. Batch experiments showed that the amount of
catalyst remaining within the reactor after 20 runs is
enough for high conversion within 1 hour. A further
continuous experiment supported this result, because an
increase of methanol from 10 to 20 equiv. raised the
conversion from 60% to 90% after 20 residence times
and a further methanol increase to 30 equiv. showed a
conversion of 95%, which could be maintained for over
30 residence times. In both cases the ee was almost
unaffected and remained at a level of 50%. Further-
more, the decline of the ee value cannot be explained by
catalyst leaching, since the uncatalyzed reaction
between anhydride 1 and 10 equiv. of methanol result-
ing in racemic product is slow (12% conversion after 24
hours). Batch experiments were conducted to investi-
gate the decline in reaction rate. The opening of anhy-
dride 1 was complete within 15 minutes in the presence
of 1 equiv. of product while 4 hours were required in
the presence of 8 equiv. of product. This indicates
product inhibition could be one reason for the rapid
decline of conversion in the continuous reaction.
Figure 1. Conversion (ꢀ) and ee ( ) values of the continu-
ous ring-opening of anhydride 1.
is changed after completion of the reaction and high
values of conversion and ee should be achieved. The
system used for the repetitive batch reaction is shown in
Scheme 4.
In Fig. 2 the ee value and conversion trends for two
repetitive batch cycles, each of 18 single runs, are given.
The reactor was charged with the polymer-bound
AQN-catalyst 5 and solvent, containing the low molec-
ular weight compounds, methanol and anhydride 1.
After completion of the reaction, the catalyst 5 was
separated from the low molecular weight compounds
by pressing the liquid through the membrane. Catalyst
If product inhibition is responsible for the decline of
both ee and conversion, a continuous reaction is not
favored because of the high product concentration
inside the reactor. A repetitive batch reaction set-up is
much more suitable since the complete reaction volume

J. Wo¨ltinger et al. / Tetrahedron Letters 43 (2002) 8531–8533
8533
of the recovered and washed catalyst showed that 2
molecules of product were attached per AQN-ligand.
This indicated that the acid attached to the catalyst is
responsible for the decrease in selectivity. Enhancement
of the washing procedure between two runs should
result in a reconstitution of the original catalyst and
high conversion and enantioselectivity for each run
should be possible.
The principle of catalyst recovery by using a polymer
attached homogeneous catalyst has been introduced in
the asymmetric opening of meso-anhydrides. By using
the set-up of a repetitive batch system, the ease of
recovery and reuse of this type of catalyst has been
demonstrated. The drawbacks of this reaction in terms
of high catalyst concentration can be compensated for
by using membrane reactor technology. On running the
asymmetric opening with the original (DHQD)2-AQN
ligand, 100 mol% of catalyst was needed to complete
the reaction within 15 minutes at room temperature to
obtain high selectivity. Calculating the catalyst
employed in a repetitive batch system with 18 cycles 5.6
mol% of catalyst was required for one single batch and
this amount would decrease even further with each
further run.
Scheme 4. Set-up for the repetitive batch reaction. The reac-
tion was performed in 10 mL toluene. 0.25 mmol anhydride 4,
2.5 mmol methanol and 0.25 mmol catalyst 3 were used in the
reaction.
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Figure 2. Conversions and ee values for two repetitive batch
reactions have been illustrated. Repetitive batch 1 (ꢀ and ꢁ)
without washing procedure between two runs and repetitive
batch 2 (" and ꢂ) with washing procedure between two
runs. Conversion and ee values have been determined by
HPLC.
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for 18 cycles. That is a significant improvement com-
pared with the continuous experiment, but the ee values
remained low (40% ee after six runs).
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