Kinetic resolution of racemic 2-(2-furyl)-2-hydroxyethyl acetate in the presence of PS lipase

Article abstract of DOI:10.1016/S0957-4166(00)00052-5

Kinetic resolution of racemic 2-(2-furyl)-2-hydroxyethyl acetate by transesterification with vinyl acetate in the presence of Amano PS lipase, yielding (1R)-1-(2-furyl)ethane-1,2-diol diacetate with 98% ee and (2S)-2-(2-furyl)-2-hydroxyethyl acetate with

Full text of DOI:10.1016/S0957-4166(00)00052-5

Tetrahedron: Asymmetry 11 (2000) 1211±1215
Kinetic resolution of racemic 2-(2-furyl)-2-hydroxyethyl
acetate in the presence of PS lipase
Janina E. Kaminska,* Krzysztof Smigielski, Danuta —obodzinska and Jozef Gora
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Institute of General Food Chemistry, Technical University of —odz, ul. Stefanowskiego 4/10, 90-924 —odz, Poland
Received 31 December 1999; accepted 4 February 2000
Abstract
Kinetic resolution of racemic 2-(2-furyl)-2-hydroxyethyl acetate by transesteri®cation with vinyl acetate
in the presence of Amano PS lipase, yielding (1R)-1-(2-furyl)ethane-1,2-diol diacetate with 98% ee and
(2S)-2-(2-furyl)-2-hydroxyethyl acetate with >99% ee, is described. # 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
The 2-furan-substituted ethane-1,2-diols with known con®guration at C-1 can serve as chiral
synthons in the preparation of modi®ed d- or l-sugar moieties (azasaccharides, deoxy-
azasaccharides) and nitrogen heterocycles, such as carbacephems, unusual amino acids, pip-
eridine and izidine alkaloids in aza-Achmatowicz reactions.1 Quite recently we reported a method
for the multigram scale preparation of homochiral (S)- and (R)-1-(2-furyl)ethanols from the
racemic alcohol by acetylation with vinyl acetate in the presence of lipases.2,3 These alcohols were
converted to (1S)- and (1R)-(2,5-dihydro-2,5-dimethoxy-2-furyl)ethanols via electrochemical
methoxylation.4 The utility of these synthons in the preparation of d- and l-aminosugars daun-
osamine and ristosamine (3-amino-2,3,6-trideoxyhexoses) has recently been demonstrated.5
Herein we describe the enzymatic resolution of racemic 2-(2-furyl)-2-hydroxyethyl acetate (‹)-
1 yielding homochiral mono- (S)-( )-1 and diacetyl (R)-(+)-2 derivatives, new potential carbo-
hydrate precursors (Scheme 1). These compounds can be converted to the corresponding hex-2-
enopyranosid-4-uloses, intermediates in the preparation of 6-hydroxy analogues of daunosamine
and ristosamine,6 both d- and l-sequences, as well as chiral synthons in other natural product
preparations following known synthetic pathways.7,8
* Corresponding author. E-mail: jekamins@snack.p.lodz.pl
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00052-5

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J. E. Kaminska et al. / Tetrahedron: Asymmetry 11 (2000) 1211±1215
1212
Scheme 1.
2. Results and discussion
Taking into account the similarity of the 2-(2-furyl)-2-hydroxyethyl acetate (‹)-1 structure to
previously resolved racemic 1-(2-furyl)ethanol, our ®rst trials were directed at the resolution of 1
via transesteri®cation with vinyl acetate (1:5 molar ratio) in carbon tetrachloride in the presence
of Lipozyme IM (immobilized lipase from Rhizomucor miehei).2 Unfortunately for this substrate
the enantioselectivity (E=4) of Lipozyme IM was found to be insucient to attain satisfactory
enantiomer separation. Searching for a more selective lipase we performed screening experiments
under the same conditions with other commercial enzymes, namely, porcine pancreas lipase
(PPL) and microbial lipases: A (from Aspergillus sp.), AY (from Candida rugosa) and PS (from
Pseudomonas sp.). With the exception of lipase A, which was inactive, all other lipases have
shown the same direction of enantioselectivity, the (R)-enantiomer being acetylated faster than
the (S). Moreover, the enantiopreference was the same as for 1-(2-furyl)ethanol,2 which means
that replacing methyl group in the side chain with hydroxymethyl group does not change the
substrate arrangement in enzyme active site. The most promising results in preliminary tests have
been found for lipase PS (Amano), which was the most active as well as being the most enantio-
selective. When the transesteri®cation was carried out in carbon tetrachloride at ambient temp-
erature for 24 h, 61% conversion was reached yielding pure enantiomer (S)-( )-1 and diacetate
(R)-(+)-2 of 63% ee (E=22).
The absolute con®guration of (R)-1-(2-furyl)ethane-1,2-diol diacetate (R)-(+)-2 and (S)-2-(2-
furyl)-2-hydroxyethyl acetate (S)-( )-1 was determined by conversion into corresponding diols by
treatment with sodium methoxide in methanol, and comparison of sign of the speci®c rotation
with literature data.9 Enantiomeric excesses were determined by GC analysis of the reaction
mixture using Chiraldex-GTA column, on which full separation of enantiomers of 2 and partial
separation of the enantiomers of 1 could be achieved.
Although lipase PS has been suciently active, the enantioselectivity factor E=22 is too low to
attain resolution for both enantiomers in a single transesteri®cation. Sometimes, changing the
acyl donor results in a signi®cant increase of enantioselectivity.10 We checked this possibility by
replacing vinyl acetate with more bulky isopropenyl acetate. The resolution was carried out in
hexane, carbon tetrachloride and tetrahydrofuran. For hexane and carbon tetrachloride the lower
enantioselectivities were observed (15±17 versus 22), while in tetrahydrofuran acetylation did not
take place at all.
Another possibility for increasing enantioselectivity of PS lipase was searching for the proper
solvent system ensuring a reasonable transesteri®cation rate together with a high enantioselectivity.
For several tested solvents of di€erent polarity (hydrocarbons, chlorohydrocarbons, ethers) E ranged
from 15 to 80. It is noteworthy that in polar solvents such as dioxane, 1,2-dimethoxyethane, or

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acetone the transesteri®cation rate is very low and conversion does not exceed 5%, while in
hydrocarbons or chlorinated solvents it reaches 25±50% at the same time.
It is generally accepted that kinetic resolution of a racemic substrate for both pure enantiomers
in a single process is possible when the enantioselectivity value is ca. 100 or higher. In our screening
the highest enantioselectivity (E=80) was reached in the mixture of hexane and tetrahydrofuran
(4:1 ratio, v/v). Therefore this solvent mixture was chosen for preparative transesteri®cations on a
multigram scale. The reaction proceeded with an acceptable rate yielding homochiral non-acetyl-
ated enantiomer (S)-( )-1 at 53% conversion. In order to obtain the second enantiomer of high
purity we decided to perform deacetylation of (R)-(+)-2 with ee>80% into the corresponding
enriched diol and again acetylate it with vinyl acetate in the presence of lipase PS. During diol
acetylation the primary hydroxyl group is acetylated ®rst, and then enantioselective acetylation of
the secondary hydroxyl group proceeds. When ca. 80% conversion was reached, diacetate (R)-
(+)-2 of 98% ee was isolated.11 We have found that lipase PS could be used in the trans-
esteri®cation process several times without change in enantioselectivity; however, activity somewhat
decreased after each run.
Comparing our method to reported asymmetric dihydroxylation12 of 2-vinylfuran in the
presence of AD-mix, the yields are in the same range, 80±90%, but diols obtained via kinetic
resolution using PS lipase are of higher purity, 98±99% ee versus 90±93% ee for dihydroxylation
products. Moreover, experimental protocol for enzymatic resolution is extremely simple (stirring
at room temperature, then ®ltration, evaporation and chromatography) and economic, because
all chemicals Ð solvent, vinyl acetate and lipase Ð can be recycled in several runs.
3. Conclusions
A convenient and e€ective two-step procedure of kinetic resolution of 2-(2-furyl)-2-hydroxy-
ethyl acetate by transesteri®cation with vinyl acetate in the presence of PS lipase providing both
homochiral enantiomers has been realised. These compounds can serve as chiral synthons in the
preparation of d- and l-3-amino-2,3-dideoxyhexoses Ð aminosugars useful in anthracycline
antibiotics synthesis.13±15
4. Experimental
4.1. General
Porcine pancreas lipase was purchased from Sigma. Lipases A, AY and PS were received from
Amano Enzyme Europe Ltd and Lipozyme IM from Novo-Nordisk. Vinyl acetate was obtained
from Fluka, all solvents reagent grade from POCH. All reagents were used as received. Prep-
arative TLC was performed on Kieselgel 60 F254 plates from Merck. Enantiomeric excesses were
determined by GC using Chiraldex G-TA column 30 mÂ0.25 mm with temperature program:
isotherm. 70ꢀC, 30 min, then to 135ꢀC at 0.5ꢀC/min. Retention times were as follows: (S)-2 Ð119.45
min; (R)-2 Ð120.72 min; (S)-1 Ð130.55 min; (R)-1 Ð131.48 min. Optical rotations were measured
using Horiba or Autopol IV (Rudolph Research) polarimeters. NMR spectra were recorded
using a Bruker 250 MHz spectrometer. All transesteri®cations were performed at room temp-
erature with magnetic stirring.

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4.2. (2S)-(2-Furyl)-2-hydroxyethyl acetate (S)-( )-1
To the solution of 17.0 g (100 mM) of (‹)-1, and 43.0 g (500 mM) vinyl acetate in the mixture
of 80 ml hexane and 20 ml THF, 1.7 g of lipase PS (Amano) was added. The suspension was
stirred at room temperature and progress of the reaction was monitored by GC. When 56%
conversion was reached (3 days), enzyme was ®ltered, and solvents together with excess of vinyl
acetate were evaporated under reduced pressure. The residue was chromatographed on silica gel
impregnated with 1% (by weight) of sodium acetate. The column was eluted ®rst with hexane and
then with hexane/acetone mixture. After solvent evaporation from fractions containing diacetate
(R)-2, 11.0 g of product with 82% ee was obtained. After solvent evaporation from fractions
containing non-reacted substrate, 8.0 g (94%) of homochiral (S)-( )-1 (ee>99% by CG) was
obtained. (S)-( )-1: [ꢀ]D 22.3 (2.61, CH2Cl2); 1H NMR (CDCl3): 2.09 (s, 3H); 2.82 (s, 1H); 4.36
(d, J 7.5 Hz, 2H) 4.95 (t, J 7.5 Hz, 1H); 6.34 (m, 2H); 7.39 (m, 1H).
4.3. (1S)-(2-Furyl)ethane-1,2-diol
Sample of (S)-( )-1 after treatment with 0.05 M MeONa in methanol at room temperature
overnight yielded quantitatively (S)-1-(2-furyl)-1,2-ethandiol, [ꢀ]D 36.1 (2.72, CH2Cl2) (lit.9 [ꢀ]D
34.3).
4.4. (1R)-(2-Furyl)ethane-1,2-diol diacetate (R)-(+)-2
To 11.0 g (52 mM) of diacetate 2 (ee 82% R) obtained from the previous experiment, 50 ml of
0.05 M MeONa in methanol was added at room temperature and the mixture was left overnight.
Then the solution was ®ltered through a silica pad and methanol evaporated under reduced
pressure yielding 6.6 g of (R)-1-(2-furyl)-1,2-ethandiol (82% ee). To the diol dissolved in the
mixture of hexane (40 ml) and THF (10 ml), 40 g (470 mM) of vinyl acetate and 0.5 g PS lipase
were added. The suspension was stirred at room temperature and monitored by GC. When ca.
80% conversion was reached (3 days), enzyme was ®ltered, and solvents together with excess of
vinyl acetate were evaporated under reduced pressure. The residue was chromatographed on
silica gel as previously yielding 8.7 g (87%) of (R)-(+)-2 (98% ee), [ꢀ]D 107.7 (1.90, CH2Cl2); [ꢀ]D
1
120.2 (0.44, CHCl3) (lit.16 [ꢀ]D 117, CHCl3); H NMR (CDCl3): 2.06 (s, 3H); 2.09 (s, 3H); 4.45
(m, 2H); 6.11 (2d, J 5 Hz, 1H); 6.38 (m, 2H); 7.41 (m, 1H, and 1.7 g of almost racemic 1).
4.5. (1R)-(2-Furyl)ethane-1,2-diol
Sample of (R)-2 after treatment with 0.05 M MeONa in methanol at room temperature over-
night yielded quantitatively (R)-1-(2-furyl)-1,2-ethandiol, [ꢀ]D 35.2 (1.12, CH2Cl2) (lit.9 [ꢀ]D 36.7).
Acknowledgements
Financial support from the Department of Food Chemistry and Biotechnology of the Technical
University of —odz is gratefully acknowledged. We thank Dr Barbara Szechner from Instytut
Farmaceutyczny in Warszawa for racemic 2-(2-furyl)-2-hydroxyethyl acetate, and Novo-Nordisk
and Amano Enzyme Europe Ltd for the generous gift of lipases.

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1215
References
1. Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 105±114.
2. Kaminska, J.; Gornicka, I.; Sikora, M.; Gora, J. Tetrahedron: Asymmetry 1996, 7, 907±910.
3. Kaminska, J.; Gora, J.; Sikora, M.; Achmatowicz, O.; Szechner, B. Polish Patent Application, P-313607, 03.04,
1996.
4. Smigielski, K.; Gora, J.; Kula, J.; Sikora, M.; Kaminska, J. Polish Patent Application, P-312118, 29.12, 1995.
5. Szechner, B.; Achmatowicz, O.; Badowska-Ros•onek, K. Pol. J. Chem. 1999, 73, 1133±1141.
6. Sammes, P. G.; Thetford, D. J. Chem. Soc., Perkin Trans. 1 1988, 111±123.
7. Drueckhammer, D. G.; Barbas, C. F.; Nozaki, K.; Wong, C.-H.; Wood, C. Y.; Ciufolini, M. A. J. Org. Chem.
1988, 53, 1607±1611.
8. Kametani, T.; Tsubuki, M.; Tatsuzaki, Y.; Honda, T. J. Chem. Soc., Perkin Trans. 1 1990, 639±646.
9. Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165±176.
10. Faber, K. Biotransformations in Organic Chemistry; Springer-Verlag: Berlin, 1997; pp. 300±326.
11. Kaminska, J.; Gora, J.; —obodzinska, D. Polish Patent Application, P-326396, 18.05, 1998.
12. Taniguchi, T.; Nakamura, K.; Ogasawara, K. Synlett 1996, 971.
13. Arcamone, F.; Bargiotti, A.; Casinelli, G.; Redaelli, S.; Di Marco, A.; Casazza, A. M.; Dasdia, T.; Necco, A.;
Reggiani, P.; Supino, R. J. Med. Chem. 1976, 19, 733.
14. Arcamone, F.; Di Marco, A.; Lazzari, E. Patent DE 2633913; Chem. Abstr. 1977, 86, 171789.
15. Baer, H. H.; Neilson, T. Can. J. Chem. 1965, 43, 840.
16. Horton, D.; Tsuchiya, T. Chem. Ind. 1966, 2011.