Enzymatic Reduction of Hydrophobic β,δ-Diketo Esters

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.

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

References and Notes

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<A NAME="RC01601SS-23">23</A>

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%.

<A NAME="RC01601SS-24">24</A>

Calculation based on the relative intensity within the following three pairs of ¹³C-signals: δ_{C-2( syn )}/δ_{C-2( anti )}, δ_{C-4( syn )}/δ_{C-4( anti )}and δ_{C-5( syn )}/δ_{C-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.

<A NAME="RC01601SS-25">25</A>

Data taken from the diastereomeric mixture, reference 28.

Procedure similar to:

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<A NAME="RC01601SS-28">28</A>

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.