Lipase-catalyzed kinetic resolution of α-β-unsaturated α'-acetoxy ketones

Article abstract of DOI:10.1016/S0957-4166(98)00006-8

The lipase-catalyzed kinetic resolutions of the α,β-unsaturated α'- acetoxy ketones 3a,b have been investigated. Of the lipases examined, CAL-B from Candida antarctica (fraction B) has been shown to be an efficient biocatalyst, which may be used effectively in preparative scale reactions.

Full text of DOI:10.1016/S0957-4166(98)00006-8

Pergamon
Tetrahedron: Asymmetry 9 (1998) 791–796
Lipase-catalyzed kinetic resolution of α,β-unsaturated
α0-acetoxy ketones
Waldemar Adam, María Teresa Díaz ∗ and Chantu R. Saha-Möller
Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
Received 23 December 1997; accepted 2 January 1998
Abstract
The lipase-catalyzed kinetic resolutions of the α,β-unsaturated α0-acetoxy ketones 3a,b have been investigated.
Of the lipases examined, CAL-B from Candida antarctica (fraction B) has been shown to be an efficient biocatalyst,
which may be used effectively in preparative scale reactions. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
In recent years, lipases have been successfully used as efficient biocatalysts for the kinetic resolution
of a wide range of chiral compounds.1 We report here on the lipase-catalyzed hydrolysis of the α,β-
unsaturated α0-acetoxy ketones 3a,b in the presence of four different lipases. This reaction provides
optically active α-acetoxy ketones 3 and α-hydroxy ketones 4, highly functionalized molecules with
a wide potential (Scheme 1). So far no general procedures for the synthesis of these compounds in
enantiomerically pure form have been reported and only a few examples of related cyclic compounds
have been resolved with lipases as catalysts.2
2. Results and discussion
The racemic enone substrates 3 were prepared by standard acetylation of the corresponding
α-hydroxy hydroperoxides3 2 by acetic anhydride and triethylamine in dichloromethane with p-
dimethylaminopyridine (DMAP) as catalyst (Scheme 1). The labile peracetate, which results from
acetylation of the hydroperoxy group, dehydrates (Kornblum–de la Mare reaction4) to give the racemic
enones 3 in 70–75% yield.
∗
Corresponding author. E-mail: Adam@chemie.uni-wuerzburg.de
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00006-8

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Scheme 1. Synthesis and enzymatic hydrolysis of the enone substrates 3a,b
The enzymatic hydrolyses were carried out in 0.1 M phosphate buffer (pH 8) with 20% methanol as
cosolvent. The results are shown in Table 1. Of the lipases tested, the best results for the resolution of the
enones 3a,b were obtained with the CAL-B lipase as catalyst (E values, which characterize the efficiency
of the resolution, up to 150).
For the substrate 3a, an ee value of 93% for the acetate and 85% for the alcohol was achieved at 52%
conversion (entry 2). In the case of derivative 3b, an ee value of 92% for the acetate and 96% for the
alcohol was obtained at 49% conversion (entry 8), at 52% conversion the acetate reached ee values >98%
(entry 10).
The lipase CAL-B exhibited a very pronounced affinity for one of the enantiomers, as evidenced by
the low amount of further conversion after the preferred enantiomer had been practically fully consumed.
Lipase PSL2 was faster than lipase CAL-B, but the ee values were moderate, even for the acetate at high
conversions (entries 6 and 13). Lipases BSL (entries 1 and 7) and PSL1 (entries 5 and 11) showed also
only moderate enantiomeric excesses for both the alcohol and acetate.
Because of the low ee values obtained for the alcohol in comparison with those for the acetate, we
carried out control experiments, which showed that the alcohol, but not the acetate, is partly racemized
under the reaction conditions. This may be explained by the equilibrium between the conjugated and
the less favored unconjugated tautomers of the hydroxy enone 4 through their enolate intermediate
(Scheme 2).
The absolute configurations were assigned by chemical correlation, in which the optically active
acetoxy ketones 3 were reduced to the corresponding literature-known 1,2-diols 5 (Scheme 3).6 Authentic
samples of the latter were obtained by horseradish peroxidase (HRP) catalyzed kinetic resolution of the
corresponding α-hydroxy hydroperoxides 2 (Scheme 3).
Comparison of the diols 5a obtained by NaBH4 reduction of the acetoxy ketone 3a and by Ph3P
reduction of the hydroperoxides 2a, whose absolute configurations have been previously established,6
established the S configuration of the stereogenic center in the acetoxy ketone 3a. The R configuration
deduced in this way for the alcohol 4a agrees with the reported data.7 Following the same procedure,
comparison of the diols 5b obtained by NaBH4 reduction of the acetoxy ketone 3b and by Ph3P reduction
of the hydroperoxides 2b, established the R configuration of the stereogenic center in the acetoxy ketone
3b. Correspondingly, the absolute configuration of the alcohol 4b is then assigned as S. The acetate 3b
and alcohol 4b are hitherto unknown and no specific rotation data are available for comparison.
The R enantiomer is preferred in the case of acetate 3a, which fits the empirical model, proposed
by Kazlauskas et al.,8 well for the kinetic resolution of secondary alcohols, based on the size of
the substituents at the stereogenic carbon center. However, the lipases examined showed an opposite

W. Adam et al. / Tetrahedron: Asymmetry 9 (1998) 791–796
793
Table 1
Lipase-catalyzed kinetic resolution of the unsaturated α-acetoxy ketones 3a,b
Scheme 2. Proposed mechanism for the racemization of the hydroxy enone 4
preference for the methyl-substituted acetate 3b. While this behavior is as yet not well understood, similar
deviations from the empirical rule have been noted in related compounds.9
In conclusion, lipase CAL-B proved to be the most efficient biocatalyst for the kinetic resolution of
the compounds 3a,b. The ee values for the alcohol 4 are not as high as expected, which is due to some
racemization under the reaction conditions. This lipase was then used for the synthesis of optically active
acetates 3 and alcohols 4 on a preparative scale (Table 2).

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Scheme 3. Chemical correlation of the optically active α-acetoxy ketones 3 with the corresponding 1,2-diols 5
Table 2
Preparative-scale lipase-catalyzed kinetic resolution of acetates 3a,b
3. Experimental
3.1. General procedure for the lipase-catalyzed hydrolysis of acetates 3a,b
To a solution of the substrate (0.2 mmol) in 0.4 mL MeOH were added 1.6 mL of 0.1 M phosphate
buffer (pH 8) and the lipase powder. The mixture was vigorously stirred at ca 20°C for the time indicated
in Table 1 and then the products were extracted with ether (3×10 mL). The organic phase was washed
with saturated aqueous NaHCO3 solution and brine and dried over MgSO4. Crude samples were analyzed
by GC and HPLC. In preparative-scale experiments (1.0–2.0 mmol) the products were separated by
preparative TLC on silica gel 60 F254 with n-hexane:ethyl acetate (80:20) as the eluent.

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3.2. (S)-(−)-4-Acetoxypent-1-en-3-one [(S)-3a]
1
Colorless oil; [α]D20=−24 (CHCl3, c 0.6, for 98% ee). H NMR (250 MHz, CDCl3): δ 6.49 (dd,
J=17.4, 10.1 Hz, 1H), 6.35 (dd, J=17.4, 2.1 Hz, 1H), 5.83 (dd, J=10.1, 2.1 Hz, 1H), 5.28 (q, J=7.0 Hz,
1H), 2.11 (s, 3H), 1.40 (d, J=7.0 Hz, 3H); 13C NMR (62.8 MHz, CDCl3): δ 196.3 (s), 170.2 (s), 131.4 (d),
130.1 (t), 73.3 (d), 20.6 (q), 16.2 (q); IR (CDCl3): ν 2991, 2939, 2875, 1740, 1712, 1616, 1457, 1447,
1406, 1373, 1290, 1243, 1048, 982 cm−1. Anal. calcd for C7H10O3 (142.1): C, 59.13; H, 7.09. Found: C,
58.85; H, 6.77.
3.3. (R)-(−)-4-Acetoxy-2-methylpent-1-en-3-one [(R)-3b]
Colorless oil; [α]D20=−8 (CHCl3, c 0.6, for 98% ee). 1H NMR (250 MHz, CDCl3): δ 5.97 (br d, J=0.9
Hz, 1H), 5.87 (q, J=1.5 Hz, 1H), 5.69 (q, J=7.0 Hz, 1H), 2.12 (s, 3H), 1.90 (dd, J=1.5, 0.9 Hz, 3H), 1.44
(d, J=7.0 Hz, 3H); 13C NMR (62.8 MHz, CDCl3): δ 198.1 (s), 170.2 (s), 141.8 (s), 125.3 (t), 70.6 (t),
20.5 (q), 17.7 (q), 17.2 (q); IR (CDCl3): ν 3100, 2990, 2963, 2930, 1735, 1691, 1630, 1450, 1373, 1277,
1246, 1148, 1096, 1049 cm−1. Anal. calcd for C8H12O3 (156.1): C, 61.51; H, 7.75. Found: C, 61.06; H,
7.35.
3.4. (R)-(−)-4-Hydroxypent-1-en-3-one [(R)-4a]
Colorless oil. The spectral characteristics were identical to those reported previously;7 [α]D20=−51
(CHCl3, c 0.6, for 98% ee).
3.5. (S)-(−)-4-Hydroxy-2-methylpent-1-en-3-one [(S)-4b]
1
Colorless oil; [α]D20=−30 (CHCl3, c 0.3, for 90% ee). H NMR (250 MHz, CDCl3): δ 5.92 (br dd,
J=1.8, 1.2 Hz, 2H), 4.89 (dq, J=7.0, 6.4 Hz, 1H), 3.56 (d, J=6.4 Hz, 1H), 1.94 (d, J=7.0 Hz, 3H): 13C
NMR (62.8 MHz, CDCl3): δ 203.8 (s), 141.1 (s), 126.5 (t), 68.5 (t), 22.6 (q), 17.8 (q); IR (CDCl3): ν
3690, 3487, 2983, 2930, 2860, 1675, 1629, 1602, 1455, 1375, 1315, 1242, 1146, 1058 cm−1
.
Acknowledgements
This work was financially supported by the Deutsche Forschungsgemainschaft (SFB 347,
‘Selektive Reaktionen Metall-aktivierter Moleküle’), the Bayerische Forschungsstiftung (Bayerischer
Forschungsverbund Katalyse — FORKAT), and the Fonds der Chemischen Industrie. M.T.D. thanks
the Alexander-von-Humboldt Foundation for a postdoctoral fellowship (1997). We are grateful to
Boehringer Mannheim GmbH for the generous gift of enzymes.
References
1. Wong, C. H.; Whitesides, G. M. Enzymes in Synthetic Organic Chemistry, Pergamon, Oxford, 1994, pp. 41–130.
2. Tanyeli, C.; Demir, A. S.; Dikici, E. Tetrahedron: Asymmetry 1996, 7, 2399–2402.
3. Adam, W.; Nestler, B. J. Am. Chem. Soc. 1992, 114, 6549–6550.
4. Kornblum, N.; de la Mare, H. E. J. Am. Chem. Soc. 1951, 73, 880–881.
5. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299.
6. Hoch, U.; Humpf, H.-U.; Schreier, P.; Saha-Möller, C. R.; Adam, W. Chirality 1997, 9, 69–74.

796
W. Adam et al. / Tetrahedron: Asymmetry 9 (1998) 791–796
7. Stammen, B.; Berlage, U.; Kindermann, M. K.; Günther, B.; Sheldrick, W. S.; Welzel, P.; Roth, W. R. J. Org. Chem. 1992,
57, 6566–6575.
8. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. J. Org. Chem. 1991, 56, 2656.
9. Adam, W.; Díaz, M. T.; Saha-Möller, C. R. Lipase-catalyzed kinetic resolution of threo-configured 1,2-diols: A comparative
study of transesterification versus hydrolysis, in press.