4th EucheMs chemistry congress

Poster Session 2
s1274
chem. Listy 106, s257–s1425 (2012)
Poster session 2 - organic chemistry
P - 0 8 2 2
dynAMiC KinetiC reSoLution of MethyL
2,3-dihydroBenzo[B]furAn-3-CArBoxyLAte
And ethyL 5-ChLoro-2,3-dihydroBenzo[B]furAn-
-3-CArBoxyLAte
P. BonGen 1 , J. PietruSzKA 1 , r. C. SiMon 2
1 Institute of Bioorganic Chemistry, Juelich, Germany
2 Chemie, Graz, Austria
Enzymatic kinetic resolution is a powerful tool for
separating enantiomers of a racemic mixture. A severe limitation
is the maximum theoretical yield of 50% in all cases, unless
racemisation of the substrate is possible. The dynamic enzymatic
kinetic resolution could in these cases overcome the disadvantage
and would thus furnish products with a very high enantiomeric
excess and in high yield. Hydrolases such as lipases are still the
preferred biocatalysts to establish dynamic enzymatic kinetic
resolution since they are readily available and – concerning the
reaction conditions – show considerable flexibility. [1]
Herein we report a method for the kinetic resolution of
racemic methyl 2,3-dihydrobenzo[b]furan-3-carboxylate and its
chlorine derivative methyl 5-chloro-2,3-dihydrobenzo[b]furan-3-
-carboxylate. After establishing a successful biocatalytic system
with outstanding results concerning ee and yield, dynamic,
enzymatic, kinetic resolutions were investigated to increase
yields up to more than 50 %. The compounds of interest were
known precursors for analgesic agent 7-benzoyl-5-chloro-2,3-
-dihydrobenzo[b]furan-3-carboxylic acid (BRL 37959). [2]
For improving enzyme screening, reversed phase HPLC
with CD detector was used to determine ee during screening. This
method allows high throughput screening because of its time
advantage compared to normal phase chiral HPLC. Especially to
find an enzyme that hydrolyses selectively ethyl 5-chloro-2,3-
-dihydrobenzofuran-3-carboxylate which affords better
yields than the corresponding methyl ester when carrying out
Friedel-Crafts acylation to come to ethyl 7-benzoyl-5-chloro-2,3-
-dihydrobenzo[b]furan-3-carboxylate, which can easily be
hydrolysed under acidic conditions to afford analgesic agent
BRL 37959.
references:
1. E.g. U. T. Bornscheuer and R. J. Kazlauskas, Hydrolases
in Organic Synthesis - Regio- and Stereoselective
Biotransformations, Wiley-VCH, Weinheim, 1999.
2. E. A. Boyle, F. R. Mangan, R. E. Markwell, S. A. Smith,
M. J. Thomson, R. W. Ward, P. A. Wyman, J. Med. Chem.
1986, 29, 894.
Keywords: dynamic kinetic resolution; chemoenzymatic;
analgesic agent;
4 th EucheMs chemistry congress
P - 0 8 2 3
diAStereoSeLeCtive SyntheSiS of
new oPtiCALLy ACtive 1-(SuBStituted
AryL)PyrroLe derivAtiveS
e. B. BottKA 1 , A. thurner 2 , f. fAiGL 2
1 Budapest University of Technology and Economics,
Department of Organic Chemistry and Tecnology, Budapest,
Hungary
2 Budapest University of Technology and Economics, MTA-BME
Organic Chemical Technology Research Group, Budapest,
Hungary
Multisubstituted 1-arylpyrroles are known intermediates of
biologically active compounds (mytomycine analogs,
pyrrolobenzoxazepines, neopyrolomycine). Synthesis of these
compounds via classical methods usually results in low yields
because of the acid sensitivity of the pyrrole ring. Application of
organometallic reagents can help one to get rid of that problem if
highly selective mono- and dimetallation methods were available
for these types of compounds.
First members of C symmetric atropisomeric 1-arylpyrrole
1
derivatives were prepared by our research group about 10 years
ago [1] . Some of these derivatives can be applied as chiral ligands
too. Later we prepared the optically pure atropisomeric
1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid
by consecutive dimetalation of 1-(2-ethylphenyl)-1H-pyrrole with
activated organometallic type base and solid carbondioxide to
provide racemic derivative followed by the resolution of
dicarboxylic acid with (S)-1-phenylethylamine [2] . Herein we
report on the examination of the regioselective metalation and
stereoselective derivative formation of the atropisomeric
dicarboxylic acid. The new derivatives were obtained in a
diastereoselective way and in good yields by consecutive
monometalation of the acid with LiDA-KOR followed by the
reactions with different reagents (for example iodomethane,
benzaldehyde, dimethylformamide, isobutyl bromide, benzyl
bromide, etc.).
Absolute configurations of successfully prepared
(+)-1-(2-(1-carboxyethyl)-6-ethylphenyl)-1H-pyrrole-2-carboxylic
acid was determined using single crystal X-ray diffraction
measurements.
The substituted dicarboxylic acids were converted into
monoesters in two different ways: selective hydrolysis of the
diester, which was formed with an excess of thionyl chloride in
ethanol or selective monoesterification.
references:
1. Fogassy, K., Harmat, V., Böcskei, Zs., Tárkányi, G., Toke, L.,
Faigl, F.: Tetrahedron: Asymmetry 11(23), 4771–4780
(2000).
2. Faigl, F.; Vas-Feldhoffer, B.; Kubinyi, M.; Pal, K.;
Tarkanyi, G.; Czugler, M.: Tetrahedron: Asymmetry 20(1),
98–103 (2009).
Keywords: Regioselectivity; Diastereoselectivity; Metalation;
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc