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Synthesis 2001(6): 0937-0942
DOI: 10.1055/s-2001-13393
SPECIALTOPIC
© Georg Thieme Verlag Stuttgart · New York

Enzymatic Reduction of Hydrophobic β,δ-Diketo Esters

Michael Wolberga, Aiguo Jia,b, Werner Hummelc, Michael Müller*a
a Institut für Biotechnologie 2, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
b Present address: Department of Pharmacy, Shandong University, Jinan, Shandong 250012, China
c Institut für Enzymtechnologie der Heinrich-Heine Universität Düsseldorf im Forschungszentrum Jülich, 52426 Jülich, Germany
Fax: +49(2461)613870; e-Mail: mi.mueller@fz-juelich.de;
Further Information

Publication History

Received 19 February 2001
Publication Date:
24 September 2004 (online)

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Abstract

The regio- and enantioselective reduction of two hydrophobic β,δ-diketo esters is presented. Enzymatic reduction of racemic tert-butyl 4-methyl-3,5-dioxohexanoate (rac-1) with alcohol dehydrogenase from Lactobacillus brevis (recLBADH) gave δ-hydroxy-β-keto ester syn-(4S,5R)-4 under dynamic kinetic resolution conditions (99.2% ee, syn:anti = 97:3, 66% isolated yield). The highly lipophilic tert-butyl-3,5-dioxoheptanoate (2) was reduced with the same sense of enantio- and regioselectivity by recLBADH. A biphasic system was applied in this case. The product, δ-hydroxy-β-keto ester (R)-9 (98.5% ee, 66% isolated yield), was converted into (R)-6-ethyl-5,6-dihydropyran-2-one [(R)-10], which is a naturally occurring fragrance.

Key words

stereoselective synthesis - asymmetric catalysis - natural products - lactones - enzymatic reduction

8

Wolberg M., Hummel W., Müller, M.; Chem.-Eur. J., in press.

13

In a hexane-buffer biphasic system the reduction of compound 2 with recLBADH proceeded to only 20% conversion after five days (NADPH-recycling with 2-propanol).

20

Hydrochloric acid was applied at 2 mol L- 1 and the washed silica gel was dried at 105 °C for 24 h.

21

If necessary, alcohols were acetylated prior to GC MS-analysis: To a CH2Cl2 solution (200 µL) of the analyte (1-5 mmol L- 1) were added trifluoroacetic acid anhydride (7 µL) and pyridine (5 µL). The vial was capped and incubated at 40 °C for 10 min.

23

In CDCl3 solution, this compound exists in three tautomeric forms according to 1H NMR spectroscopy (20 °C). In DMSO-d 6, one of the two enol forms is suppressed to approx. 5%.

24

Calculation based on the relative intensity within the following three pairs of 13C-signals: δC-2( syn )/δC-2( anti ), δC-4( syn )/δC-4( anti )and δC-5( syn )/δC-5( anti )(average value; maximum deviation ±8%). Signals of the enol forms were ignored since it can be assumed that both diastereomers undergo enolization to a similar extent.

25

Data taken from the diastereomeric mixture, reference 28.

28

Lactone syn/anti-rac-6 was prepared from compound syn/anti-rac- 4 according to the general procedure II. Compound syn/anti-rac-4, in turn, was prepared from tert-butyl acetate and syn/anti-rac-8 [12] c as described for the (4R,5S)-stereo-isomer.