Dynamic kinetic resolution of racemic tropic acid ethyl ester and its derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.03.143

The dynamic kinetic resolution of racemic mixtures of tropic acid ethyl ester under substrate racemizing conditions was studied using lipase PS with a ruthenium catalyst. Isopropenyl acetate was used as an acyl donor, since it was found to be compatible w

Full text of DOI:10.1016/j.tetlet.2007.03.143

Tetrahedron Letters 48 (2007) 3875–3878
Dynamic kinetic resolution of racemic tropic acid ethyl ester
and its derivatives
Mary Rose Atuu and M. Mahmun Hossain*
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Received 7 February 2007; revised 19 March 2007; accepted 26 March 2007
Available online 30 March 2007
Abstract—The dynamic kinetic resolution of racemic mixtures of tropic acid ethyl ester under substrate racemizing conditions was
studied using lipase PS with a ruthenium catalyst. Isopropenyl acetate was used as an acyl donor, since it was found to be compatible
with both catalysts; this resulted in an efficient dynamic kinetic resolution. With this process, a variety of racemic tropic acid ethyl
esters were transformed to optically active acetoxy-2-arylpropionic acid ethyl esters with 60–88% yields and 53–92% ee.
ꢀ 2007 Elsevier Ltd. All rights reserved.
(S)-(À)-Tropic acid is an important building block for
biologically active tropane alkaloids, such as hyoscya-
mine and scopolamine1 (Fig. 1). The use of these alka-
loids has its roots in ancient times and they continue
to be valuable drugs in the pharmaceutical field. Scopol-
amine is used as an anesthetic during surgery, for treat-
ment of mental illness and as a vomiting inhibitor.2
Hyoscyamine is used to treat cardiacarythmia and also
as an anesthetic.3 Motofen,4 which contains difenoxin
hydrochloride and atropine sulfate, is used as adjunctive
therapy in the management of acute diarrhea. Atrovent5
is used to treat chronic bronchitis and emphysema. Fur-
thermore, the presence of the two functional groups
(alcohol and ester) in the tropic acid greatly aids in the
further modification of the molecule, thus permitting
several important derivatives to be made from this single
chiral building block. Given there are many important
uses for chiral tropic acid, an efficient method for syn-
thesizing this compound is greatly desired.
During a kinetic resolution process, the maximum yield
of the desired enantiomer (starting from a racemate)7–9
is 50%. This aspect tends to make kinetic resolution a
costly process since half of the material must be
discarded or recycled. To overcome this limitation, the
dynamic kinetic resolution (DKR) process allows for
the complete transformation of a racemic mixture into
a single enantiomer. Essentially, the DKR process
comprises kinetic resolution with an additional feature:
in situ racemization of the starting material, which is
usually achieved via chemocatalaysis8–11 As a result, it
is possible to obtain the desired isomer in yields
approaching 100%.
DKR is a well investigated area, in particular, with race-
mic secondary alcohols where the hydroxy group is
bound to a stereogenic carbon center.7–10 In this Letter,
we report the first successful dynamic kinetic resolution
of a racemic primary alcohol (tropic acid ethyl ester)
and its derivatives via enzymatic acylation and catalytic
racemization.
Recently, we have reported the first lipase-catalyzed
kinetic enzymatic resolution of tropic acid ethyl ester
and its derivatives in high yield and with excellent
% ee (Scheme 1).6 Kinetic resolution is generally defined
as a process, where the two enantiomers of the racemic
mixture are transformed into products at different
rates.7,8 Therefore, in an efficient enzymatic resolution
one of the enantiomers of the racemate is selectively
transformed to product, whereas the other is left behind.
Since metal catalysts have been effectively used for
racemization of enantiomers during kinetic resolution
by enzymes, we decided to use this same approach in
our DKR method. Thus we used the most effective com-
plex hydrogen7–9,11,12 transfer metal catalyst 1 (Scheme
2) for racemization of optically pure tropic acid ester.
Catalyst 1 was readily synthesized by a known proce-
dure.8–13 Preliminary experiments indicated that chiral
tropic acid ethyl ester 2a undergoes complete racemiza-
tion in 24 h by the metal catalyst (substrate to cata-
lyst ratio is 50–1). Although the mechanistic details
*
Corresponding author. Tel.: +1 414 229 6698; fax: +1 414 229
5530; e-mail: mahmun@uwm.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.143

3876
M. R. Atuu, M. M. Hossain / Tetrahedron Letters 48 (2007) 3875–3878
CH3
H3C
N
N
O
H
O
H
O
O
HO
O
O
H
H
H
CH2OH
CH2OH
CH2OH
S-Tropic acid
Scopolamine
Hyoscyamine
CH(CH3)2
+
H3C
N
H
Br-H2O
O
O
H
CH2OH
®
Atrovent
H3C
N
HO
CN
O
.HCl
H
O
N
H2SO4.H2O
O
H
®
CH2OH
Difenoxin Hydrochloride
®
Atropine Sulfate
Figure 1.
COOEt
CH2OH
COOEt
CH2OAc
COOEt
CH2OH
Lipase PS
R
R
+
R
(R)-(+)-2
38-48% yield, 55--99% ee
OCOCH3
(S)-(-)-3
30-49% yield, 50-98% ee
( )-2
molecular sieves
R = H, CH3, OCH3, Br, Cl, F
Scheme 1.
concerning the racemization of tropic acid ethyl ester are
not fully studied, based on studies done by Casey,13
Ba¨ckvall10e and Shvo12a on hydrogen transfer reactions
involving catalyst 1, we propose the mechanism outlined
in Scheme 2. We think, first catalyst 1 dissociates to
form the active catalyst 4 and ruthenium hydride com-
plex 5. The active catalyst 4 then dehydrogenates the
tropic acid ethyl ester to form 6, which readily under-
goes tautomerization to give 3-hydroxy acrylate 7. Acry-
late 7 undergoes reduction (via aldehyde) by metal
complex 5 to give the racemic tropic acid ethyl ester
and regenerates catalyst 4 (Scheme 2).
After screening several acylating reagents,8,14,15 we have
chosen isopropenyl acetate as an acyl donor since it gave
the best results. The common acylating agent, vinyl ace-
tate inhibits the activity of the metal catalyst by forming
acetaldehyde during the acylation step which unfortu-
nately competes with the oxidized substrate during
hydrogenation.7,14 Whereas the use of isopropenyl ace-
tate from which acetone is formed in the acylation
step7,14 showed a similar trend, but to a much lower ex-
tent than vinyl acetate. Finally, the combination of cat-
alyst 1 with the lipase PS and isopropenyl acetate as an
acyl donor was selected for the DKR of the tropic acid

M. R. Atuu, M. M. Hossain / Tetrahedron Letters 48 (2007) 3875–3878
3877
for 5 min and stirred at 40–45 ꢁC for 24 h under argon.
The enzyme was then filtered off and washed with tolu-
ene (3 · 5 mL). The toluene phases were combined and
the solvent was removed under reduced pressure, and
the product was purified by flash chromatography (pen-
tane/ethyl acetate, 95/5) to yield 62.37 mg, 0.264 mmol
(88% yield) of 3-acetoxy-2-phenyl propionic acid ethyl
ester 3a (90% ee) (Table 1, entry 1).
O
H
H
1
O
Ph
Ph
Ph
Ph
Ru
Ph
Ru
Ph
Ph
Ph
CO
OC
CO
CO
Ph
O
Ph
Ph
OC
H
Ph
Ru
After successfully resolving the tropic acid ethyl ester in
high yield and high ee, various tropic acid ethyl ester
H
CO
Ph
Ru
5
COOEt
CH2OH
O
COOEt
Table 1. Kinetic resolution of ( )-2 tropic acid ethyl esters (primary
alcohol) with Lipase PS on Celite support coupled with ruthenium-
catalyzed racemization
Ph
CH2OH
Ph
Ph
OC
(+)-2a
Substrate
Product
Yield % ee of
_
(+)
-2a
(%)
(S)-(À)
CO
4
COOEt
CH2OH
COOEt
CH2OAc
5
88
90a
COOEt
CHO
5
COOEt
CHO
3a
2a
2b
3b
COOEt
CH2OH
COOEt
CH2OAc
(+)-6
_
H3CO
H3CO
(+)
-6
COOEt
OH
75
75
92a
OCH3
OCH3
H
2c
3c
7
COOEt
CH2OH
COOEt
CH2OAc
95a
Scheme 2.
H3CO
H3CO
ethyl ester. Under these conditions, the racemic tropic
acid ethyl ester is resolved to (S)-3-acetoxy-2-phenyl-
propionic acid ethyl ester 3a and (R)-tropic acid ethyl
ester 2a. At the same time, (R)-2a enantiomer undergoes
racemization by catalyst 1 (Scheme 3) and is subse-
quently resolved again until all the remaining tropic acid
ethyl ester is consumed. To a solution of ( )-2a
(58.274 mg, 0.30 mmol) in dry toluene (6 mL) under
argon, ruthenium catalyst 1 (24.5 mg, .018 mmol) and
lipase PS (65 mg) on celite support (10 mg) were added
along with isopropenyl acetate (120 mg, 1.20 mmol.).
The resulting reaction mixture was bubbled with argon
2d
3d
COOEt
CH2OH
COOEt
CH2OAc
73
84
80a
H3C
H3C
CH3
CH3
2e
3e
COOEt
COOEt
61b
CH2OH
CH2OAc
H3C
H3C
2f
3f
COOEt
CH2OH
COOEt
CH2OAc
70
81a
Br
Br
COOEt
OCH3
OCH3
CH2OAc
2g
3g
(S)-(-)-3a
COOEt
COOEt
COOEt
60
68
53b
CH2OH
CH2OAc
Lipase PS
CH2OH
Br
Br
COOEt
OAc
F
F
( )-2a
COOEt
CH2OAc
Cl
COOEt
CH2OH
Cl
CH2OH
72b
(R)-(+)-2a
2h
3h
a The % ee was determined by analysis of the 1H NMR spectrum of its
(R)-(À)-a-methoxyphenyl acetic acid derivative as described in our
earlier paper.6
b % ee was determined from optical rotation using known reported
values.6
[Ru]2
1
Scheme 3.

3878
M. R. Atuu, M. M. Hossain / Tetrahedron Letters 48 (2007) 3875–3878
derivatives 2b–h6 were subjected to the DKR reaction
conditions in order to investigate the scope of this pro-
cess (Table 1). In all cases, racemic substrates 2b–h were
completely consumed, and chiral products were isolated
in good to high yields (Table 1). In addition, the enantio-
selectivities for the product were generally high and
similar to those reported from our kinetic resolution
process.6
7. (a) Serra, S.; Brenna, E.; Fuganti, C.; Maggioni, F.
Tetrahedron: Asymmetry 2003, 14, 3313; (b) Kawanami,
Y.; Itoh, K. Chem. Lett. 2005, 34, 682; (c) Ferraboschi, P.;
Rezaelahi, S.; Verza, E.; Santaniello, E. Tetrahedron:
Asymmetry 1998, 9, 2193; (d) Balint, J.; Kiss, V.; Egri, G.;
Kalai, T.; Demeter, A.; Balog, M.; Fogassy, E.; Hideg, K.
Tetrahedron: Asymmetry 2004, 15, 671; (e) Morrone, R.;
Piatttelli, M.; Nocolosi, G. Eur. J. Org. Chem. 2001, 1444;
(f) Levy, L. M.; Dehli, J. R.; Gotor, V. Tetrahedron:
Asymmetry 2003, 14, 2053.
It is noteworthy to mention that our process is simple;
no external hydrogen source is needed for very good
to excellent yields and ee %. In most DKR methods
involving chiral secondary alcohols, an external hydro-
gen source is used to enhance yields and enantioselecti-
vies.10,12 In addition, most of these the DKR proceses
were carried out at higher temperatures (60–80 ꢁC) to
speed up the racemization step.10,12 Our DKR process
eliminates the need for an external hydrogen source or
higher temperature to obtain very good yields of prod-
ucts. One reason for the overall simplicity of our
DKR process may lie in the use of a more reactive pri-
mary alcohol (easier to dehydrogenate than secondary
alcohol) and formation of an aldehyde (easier to hydro-
genate than ketone). Further studies using different
hydrogen donors at different temperatures in order to
optimize yields and enatioselectivities of this DKR pro-
cess are underway.
8. (a) Kiebasinski, P.; Omelanczuk, J.; Mikolaczyk, M.
˜
Tetrahedron: Asymmetry 1998, 9, 3283; (b) Kagan, H.
B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249; (c) Keith,
J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal.
2001, 343, 5; (d) Choi, Y.-K.; Kim, Y. H.; Nam, S. H.;
Shin, S. T.; Kim, M.-J.; Park, J. Angew. Chem., Int. Ed.
2002, 41, 2373; (e) Choi, Y. K.; Suh, J. H.; Lee, D.; Lim, I.
T.; Jung, J. Y.; Kim, M. J. J. Org. Chem. 1999, 64, 8423;
(f) Morgan, B.; Bydlinky, G.; Dodds, D. R. Tetrahedron:
Asymmetry 1995, 6, 1765; (g) Persson, B. A.; Larsson, A.
L. E.; Ray, M. L.; Ba¨ckvall, J.-E. J. Org. Chem. 1999, 121,
1645; (h) Kirchner, G.; Scollar, M. P.; Klibanov, A. M. J.
Am. Chem. Soc. 1985, 107, 7072; (i) Strauss, U. T.; Felfer,
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`
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2001, 3, 1209; (f) Chowdbury, R. L.; Ba¨ckvall, J.-E. Chem.
Commun. 1991, 1063.
In conclusion, we have demonstrated that a ruthenium
catalyst in combination with enzymatic acylation, re-
sults in racemization and a full transformation of tropic
acid ester (primary alcohol) 2a–i to 3-acetoxy-2-phenyl
propionic acid ethyl ester 3a–i in good yield and good
% ee. Currently, we are working to convert these chiral
3-acetoxy-2-phenyl propionic acid esters into chiral 2-
aryl propionic acids. Many of these chiral 2-aryl propa-
noic acids such as ibuprofen and naproxen are impor-
tant non-steroidal anti-inflamatory drugs (NSAIDs).16
10. (a) Almeida, M. L. S.; Kocovsky, P.; Ba¨ckvall, J.-E. J.
`
Org. Chem. 1996, 61, 6587; (b) Pamies, O.; Ba¨ckvall, J.-E.
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Ji, A.; Wolberg, M.; Hummel, W.; Wandrey, C.; Muller,
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Acknowledgement
Thanks to Amano company for providing us with
enzymes lipases PS.
13. Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.;
Kavana, M. J. Am. Chem. Soc. 2001, 123, 1090.
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