Prochiral ketones reduction with yeast

Yeast reductions have provided the synthetic organic chemist with highly versatile methods to prepare chiral alcohols from prochiral ketones of which Saccharomyces cerevisiae (baker s yeast) is the most commonly used biocatalyst. In addition to prochiral ketone reductions, hundreds of... 

Chiral alcohols are valuable products mainly as building blocks for pharmaceuticals or agro chemicals or as part of chiral catalysts. Cheap biotransformation methods for the selective reduction of particular ketone compounds are known for many years rather catalyzed by fermentation than with isolated enzymes. Products prepared with whole cells such as baker s yeast often lack high enantioselectivity and there were several attemps to use isolated enzymes. Resolution of racemates with hydrolases are known in some cases but very often the reduction of the prochiral ketone using alcohol dehydrogenases are much more attractive. 

Reduction of symmetrical and prochiral 1,3-diketones with yeast gives optically active 3 hydroxy ketones, which are useful chiral building blocks in organic synthesis. 

Our synthesis started from hydroxy ketone B (Figure 5.31), which was obtained by asymmetric reduction of prochiral diketone A with fermenting baker s yeast.38 The key step in the present synthesis was the ring formation by intramolecular alkylation of C to give D. To obtain C, the enfifo-hydroxy group of B was first epimerized via retro-aldol/aldol by treatment with p-toluenesulfonic acid in carbon tetrachloride. The tricyclic intermediate D was converted to (+)-pinthunamide (146), mp 187-189°C, [a]D215 = +60 (EtOH), which was identical with the natural product. Its absolute configuration was thus determined as depicted in 146.39... 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

In 1985, we reported that reduction of a prochiral 1,3-diketone A (Figure 3.6) with fermenting baker s yeast (Saccharomyces cerevisiae) was enantioselective to give (5)-hydroxy ketone B of 98-99% ee.26 I noticed that the Baeyer-Villiger oxidation of B would furnish (S)-hydroxylactone, a building block synthetically equivalent to the terminal epoxide moiety of (+)-JH III. This idea was used for the synthesis of (+)- and (-)-JH III in 1987.27... 

Reduction of prochiral 1,3-diketone A with baker s yeast gives hydroxy ketone B of 99% ee.10 The ketone B was converted to unsaturated ketone C, which was treated with (Z)-l-propenylmagnesium bromide in the presence of cerium(III) chloride to give a mixture of D and E. This mixture was directly subjected to oxy-Cope rearrangement to give F from D. The exo-isomer E was recovered unchanged. 

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