Organocatalytic racemization of α-aryl propionates in the presence of water

Article abstract of DOI:10.1080/00397911.2011.587081

An organocatalytic method for the racemization of α-aryl propionates, which proceeds even in the presence of an aqueous phase, has been developed, thus fulfilling a prerequisite for a dynamic kinetic resolution of corresponding esters with hydrolase as a biocatalyst. The desired racemization of ethyl 2-phenylpropionate and 2-ibuprofen ethyl ester as substrates has been achieved in a two-phase system. As preferred organocatalysts for the racemization, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) have been used. Copyright Taylor & Francis Group, LLC.

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Organocatalytic Racemization of α-Aryl
Propionates in the Presence of Water
Maria Alfaro Blasco a & Harald Gröger a
a Department of Chemistry and Pharmacy, University of
Erlangen–Nürnberg, Erlangen, Germany
Accepted author version posted online: 20 Jan 2012.Version of
record first published: 05 Sep 2012.
To cite this article: Maria Alfaro Blasco & Harald Gröger (2013): Organocatalytic Racemization of α-
Aryl Propionates in the Presence of Water, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 43:1, 9-15
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Synthetic Communications1, 43: 9–15, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.587081
ORGANOCATALYTIC RACEMIZATION OF a-ARYL
PROPIONATES IN THE PRESENCE OF WATER
¨
Maria Alfaro Blasco and Harald Groger
Department of Chemistry and Pharmacy, University of Erlangen–Nu¨rnberg,
Erlangen, Germany
GRAPHICAL ABSTRACT
Abstract An organocatalytic method for the racemization of a-aryl propionates, which
proceeds even in the presence of an aqueous phase, has been developed, thus fulfilling a
prerequisite for a dynamic kinetic resolution of corresponding esters with hydrolase as a
biocatalyst. The desired racemization of ethyl 2-phenylpropionate and 2-ibuprofen ethyl ester
as substrates has been achieved in a two-phase system. As preferred organocatalysts for the
racemization, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) have been used.
Keywords Amines; carboxylic acid esters; esters; organocatalysis; racemization
INTRODUCTION
The synthesis of a-aryl propionates is of pharmaceutical importance because of the
use of representatives of this product class as nonsteroidal anti-inflammatory
drugs.[1] Although most of these so-called profen-type molecules 1 (Fig. 1) are pro-
duced in racemic form, enantiomerically pure drugs such as naproxen [(S)-2] and
dexibuprofen [(S)-3] are also known.
Accordingly, the search for enantioselective approaches to these molecules has
attracted many chemists and resulted in numerous valuable syntheses.[1] A favored
(and industrially relevant) synthetic concept is still based on resolution of racemates,
which are easily accessible compounds. Besides ‘‘classic’’ chemical resolution via
Received April 30, 2011.
Address correspondence to Harald Gro¨ger, Faculty of Chemistry, Bielefeld University,
Universita¨tsstraße 25, 33615 Bielefeld, Germany (present address). E-mail: harald.groeger@uni-bielefeld.de
9

¨
M. ALFARO BLASCO AND H. GROGER
10
Figure 1. Profens and enantiomerically pure representatives thereof.
diastereoselective formation of salts pairs (thus requiring a stoichiometric amount
of a chiral auxiliary),[2,3] several efficient enzymatic resolutions have been
developed.[4] The extension of such enzymatic resolutions toward the more attract-
ive dynamic kinetic resolution processes has been successful, but typically thioe-
sters were used as substrates.[5] This is due to the fast racemization of thioesters,
whereas the tendency of ‘‘normal’’ esters to racemize in aqueous medium is signifi-
cantly lower.[6] On the other hand, the use of thioesters is less attractive from an
economic perspective because their preparation is more laborious. Accordingly,
racemization methods for readily available alkyl esters under conditions that
enable a combination with enzymatic ester hydrolysis in water, are desirable. A
proof of concept for such a racemization in combination with an enzymatic
hydrolysis in a two-phase medium has been reported based on the use of sodium
hydroxide (0.5 M) as a base.[7] In spite of a high pH value, the resulting dynamic
kinetic resolution with a lipase proceeds efficiently.[7a] A drawback of this method,
however, is the potential of highly concentrated NaOH solutions to undergo not
only the desired racemization but also undesired cleavage of the ester substrate
as a side reaction besides causing enzyme deactivation as an additional drawback.
In the following, we report our studies on the development of an organocatalytic
method for the racemization of a-aryl propionates in the presence of an aqueous
phase as an alternative racemization method with potential to suppress side reac-
tions and cause enzyme deactivation to a lesser extent.
RESULTS AND DISCUSSION
As model compounds for our study we used the esters (S)-4 and (R)-4 or (S)-5
as substrates, and organic nitrogen-type Lewis bases were chosen as potential orga-
nocatalysts for their racemization. Initially a catalyst screening was performed for
the racemization of the ethyl ester (R)-4 (35% ee) in ethyl acetate at room temperature
(Fig. 2). It turned out that the bases 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) led to a significant racemization after 3
days, leading to the product (R)-4 in the desired low enantiomeric excess of 2% ee in
both cases.
Racemization proceeds in a comparable fashion also in organic solvents other
than ethyl acetate. This has been demonstrated for the base DBU with a significant
racemization of (S)-4 (>99% ee) after 24 h at room temperature in methyl tert-butyl
ether (MTBE; 7% ee, Table 1, entry 1). Because MTBE was considered as a more
attractive solvent for enzymatic ester hydrolysis compared to EtOAc (because of
the lack of an ester group) and because the ready availability of MTBE as a bulk

ORGANOCATALYTIC RACEMIZATION
11
Figure 2. Organocatalyst screening for the racemization of (R)-4.
Table 1. Organocatalytic racemization of ethyl (S)-2-phenylpropionate
Entrya
Organocat. (equiv.)
Organic solvent
Water [%[v=v))
T (ꢀC)
t (h)
ee (4) (%)b
1c
2
DBU (0.75)
DBU (1.42)
DBU (1.42)
TBD (1.42)
TBD (1.42)
TBD (1.42)
TBD (1.42)
TBD (1.42)
TBD (1.00)
TBD (1.00)
MTBE
ETBE
ETBE
ETBE
ETBE
MTBE
MTBE
ETBE
MTBE
MTBE
0
0
rt
24
4
7
42
2
60
60
60
60
rt
3
0
24
4
4
0
1
5
0
24
5
0
6d
7d
8d
9e,f
10e,f
50
50
50
5
94
90
65
6
rt
17
17
4
60
rt
5
rt
17
0
aThe experimental protocol is given in the experimental section.
bDetermined by chiral HPLC.
cSubstrate concentration: 0.20 M.
dpH of reaction medium: 13.
eSubstrate concentration: 0.23 M.
fpH of reaction medium: ca. 14.

¨
M. ALFARO BLASCO AND H. GROGER
12
chemical and its environmental advantages, this solvent (or its homologue ethyl
tert-butyl ether, ETBE) was used in the following as the preferred organic phase.
When studying the influence of the temperature on the racemization rate, a signifi-
cant increase was observed at an elevated temperature of 60 ꢀC (entry 2). In this
experiment ETBE was chosen as a solvent because of its higher boiling point in
comparison with MTBE. The racemization of (S)-4 (>99% ee) proceeded faster at
60 ꢀC than at 25 ꢀC with 2% ee compared to 7% ee after 24 h when using DBU as
an organocatalyst (entries 1 and 3). A further improvement of the racemization rate
was found when using TBD with a nearly complete racemization after 4 h (1% ee
compared to 42% ee when using DBU; entries 2 and 4). After 24 h complete racemi-
zation of (S)-4 (>99% ee) was observed with TBD (entry 5).
Because of our interest in combining the racemization step with an enzymatic
hydrolysis of substrates of type rac-4-5, we studied the racemization in an aqueous=
organic two-phase medium as a (potentially) suitable reaction medium for such a
process. Using TBD as a base (0.14–0.20 M) resulted in a pH being in the range
of ca. 13–14 in these mixtures (entries 6–10). The presence of water in the reaction
system initially turned out to have a strong negative impact on the TBD-catalyzed
racemization. When using a solvent mixture of water [50%(v=v)] and MTBE
[50%(v=v)] at room temperature, a low racemization rate for (S)-4 (>99% ee) with
94% after 5 h and 90% after 17 h was observed (entries 6 and 7). An improved but
still unsatisfactory racemization was observed at an enhanced temperature of
60 ꢀC in a water=ETBE two-phase system [50%(v=v) of each solvent] with 65% ee
after 17 h (entry 8).
A significant improvement in terms of racemization rates was achieved when using
two-phase systems with a minimized amount of water (entries 9 and 10). For example,
we were pleased to find that a solvent mixture of water [5%(v=v)] and MTBE [95%(v=v)]
led to a rapid racemization with 6% ee after 4 h when starting from enantiomerically
pure (S)-4 (>99% ee) in the presence of TBD (entry 9). Thus, a method has been realized
that enables the racemization in the presence of an aqueous phase and at room tempera-
ture. These criteria are of importance when considering a combination with an
(enantioselective) hydrolase towards a dynamic kinetic resolution in water in the future.
Moreover, similar experiments were carried out using the ibuprofen ester
derivative (S)-5 (>99% ee) as a substrate (Table 2). For the racemization of substrate
(S)-5, TBD was chosen as a catalyst. After performing the racemization in a
one-phase system consisting of MTBE at 25 ꢀC free-TBD showed the greatest
activity as is underlined by the low enantiomeric excess of 8% ee and 3% ee for 5 after
2 and 4 h, respectively (Table 2, entries 1 and 2). Extension of reaction time to 8 h led
to a complete racemization of the substrate (entry 3). Furthermore, the racemization
of substrate (S)-5 also proceeds completely when reducing the catalyst amount from
1 to 0.13 equivalents (entries 3 and 4).
Next, the racemization of substrate (S)-5 in a two-phase system was studied to
establish a DKR process with this type of substrate. However, when carrying out the
racemization of (S)-5 in a two-phase system consisting of a water=MTBE mixture
[1:4 (v=v)], unfortunately an unsatisfactory racemization was observed with 90%
ee remaining after 4 h (entry 5).
Encouraged by the positive results for substrate (S)-4 with a low amount of
water, in an analogous fashion the amount of water in the two-phase system was

ORGANOCATALYTIC RACEMIZATION
13
Table 2. Organocatalytic racemization of (S)-ibuprofen ethyl ester
Entrya
Organocat. (equiv.)
Organic solvent
Water [%(v=v)]
T (ꢀC)
t (h)
ee (5) (%)b
1
2
3
4
5
6
7
TBD (1.00)
TBD (1.00)
TBD (1.00)
TBD (0.13)
TBD (1.00)
TBD (1.00)
TBD (1.00)
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
0
0
25
25
25
25
25
25
25
2
4
8
8
4
4
8
8
3
0
0
0
0
20
5
90
12
1
5
aThe experimental protocol is given in the experimental section
bDetermined by chiral HPLC.
minimized for the racemization of (S)-5. We were pleased to find a significant
racemization even at room temperature when using a two-phase system, consisting
of water=MTBE [1:19 (v=v)] as reaction media. Under these reaction conditions
the racemization of substrate (S)-5 proceeded rapidly, leading to 12 and 1% ee after
4 and 8 h, respectively (entries 6 and 7).
SUMMARY
In conclusion, we have developed an organocatalytic method for the racemiza-
tion of a-aryl propionates that proceeds in the presence of an aqueous phase, thus
fulfilling a prerequisite for a dynamic kinetic resolution of alkyl esters with a hydro-
lase as a biocatalyst. As preferred organocatalysts for the racemization, DBU and
TBD have been used. A focus of the future work will be on (i) an enzyme screening
for a hydrolase, which is enantioselective in the resolution of a-aryl propionates and
tolerates the presence of DBU and TBD as catalysts for the racemization step, and
(ii) the development of a chemoenzymatic dynamic kinetic resolution process of alkyl
esters of a-aryl propionates in water with DBU and TBD as bases.
EXPERIMENTAL
General Procedure for the Organocatalytic Racemization of (S)-4
An Eppendorf tube (2 mL) was charged with (S)-4 (0.07–0.23 mmol), and the
solvent mixture (see Table 1) was added until the desired substrate concentration
was obtained. After adding the organocatalyst (for the amount, see Table 1), the
reaction mixture was agitated with a thermomixer at 500 rpm at room temperature
or 60 ꢀC (see Table 1). Samples were taken after a certain reaction time, and each
sample was filtered over silica gel using CH2Cl2 as an eluent. Then, the solvent

¨
M. ALFARO BLASCO AND H. GROGER
14
was removed in vacuo, and the enantiomeric excess of the resulting compound 4 was
determined by chiral HPLC.
General Procedure for the Organocatalytic Racemization of (S)-5
An Eppendorf tube (2 mL) was charged with (S)-5 (0.23 mmol), and the solvent
mixture (see Table 2, 1 mL) was added. After adding the organocatalyst (0.23 mmol),
the reaction mixture was agitated with a thermomixer at 500 rpm and 25 ꢀC. Samples
were taken after a certain reaction time, and each sample was filtered over silica gel
using CH2Cl2 as an eluent. Then, the solvent was removed in vacuo, and the enan-
tiomeric excess of the resulting compound 5 was determined by chiral HPLC.
ACKNOWLEDGMENTS
We thank Evonik Degussa GmbH for generous support. M.A.B. thanks the
German Academic Exchange Service (Deutscher Akademischer Austausch Dienst,
DAAD) for a scholarship.
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