Access to Wieland−Miescher Ketone in an Enantiomerically Pure Form by a Kinetic Resolution with Yeast-Mediated Reduction

Abstract

Both enantiomers of Wieland-Miescher ketone [3,4,8, 8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione], in a highly enantiomerically enriched form, became readily available by a newly developed kinetic resolution with yeast-mediated reduction. From a screening of yeast strains, Torulaspora delbrueckii IFO 10921 was selected. The collected cells of this strain, obtained by an incubation in a glucose medium, smoothly reduced only the isolated carbonyl group of the (S)-enantiomer, while the (R)-enantiomer remained intact. Starting from both enantiomers ( approximately 70% ee) prepared by an established proline-mediated asymmetric Robinson annulation, the reduction with T. delbrueckii gave the (R)-enantiomer (98% ee) and the corresponding alcohol (4aS,5S)-4,4a, 5,6,7,8-hexahydro-5-hydroxy-4a-methyl-2(3H)-naphthalenone (94% ee, 94% de) in preparative scale in nearly quantitative yields. An approach for the asymmetric synthesis of the Wieland-Miescher ketone was also successful. 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione, the prochiral precursor, was reduced with this strain to give a cyclic acetal form of (2S, 3S)-3-hydroxy-2-methyl-2-(3-oxobutyl)cyclohexanone, in a stereomerically pure form.

Enantiomerically Pure Octahydronaphthalenone and Octahydroindenone: Elaboration of the Substrate Overcame the Specificity of Yeast‐Mediated Reduction

“…The reduction of isolated carbonyl groups so far consistently observed in the substrates (1,3,4,6) was suppressed, and the 1,4-conjugate reduction [10] of the a,b-unsaturated carbonyl group proceeded as shown in Scheme 2. This enzyme showed not only enantiofacial selection, but also enantiomeric kinetic resolution, and both the product (1S,5R)-12 and the recovered substrate (R)-7 were obtained in enaniomerically pure state (Table 2, entry 3).…”

“…[5] In the subsequent years, Inayama, Shimizu and co-workers extensively studied the substrate specificity on the related compounds. [6] In turn, recently, Kodama applied baker×s yeast reduction to the Wieland±Miescher ketone (1) and its hydroindenone analogue, Hajos±Parrish ketone (4). [7] Our first candidates were the analogous substrates …”

“…[1] The enantiomerically enriched products of this kinetic resolution have been utilized as the starting material for naturally occurring terpenoids. [2,3] Recent efforts towards microorganismand enzyme-mediated preparation of mono-and bicyclic chiral building blocks of natural product synthesis [4] prompted us to investigate the scope and limitation of this yeast-mediated reduction.…”

Access to Enantiomerically Pure Intermediates for (−)-Geosmin Synthesis Starting from (4aS,5S)-4,4a,5,6,7,8-Hexahydro-5-hydroxy-4a-methyl-naphthalen-2(3H)-one

“…The IR and NMR spectra of 6a were identical with those reported previously. 10) (4aS,8S,8aS)-2,2-Ethylenedioxy-1,2,3,4,4a,7,8,8a-octahydro-8,8a-methano-4a-methylnaphthalene (7). A mixture of 6a (96.7 mg, 0.406 mmol), pyridine (6 ml) and chloromethanesulfonyl chloride (196 mg, 1.32 mmol) was stirred for 14 h at room temperature.…”

“…5) We report here scalable approaches toward the reported two key intermediates [2a and 3a], 5,6) starting from (4aS,5S )-4,4a,5,6,7,8-hexahydro-5-hydroxy-4a-methylnaphthalen-2(3 H )-one (4) prepared by the reported yeast-mediated reduction of the racemic Wielnd-Miescher ketone. 7) First, according to Heathcock's procedure, 8) alcohol 4 was converted to hydroxy ketal 5. To our disappointment, stereoselective cyclopropanation with the zinc-copper couple 9) reported by Grieco and co-workers 10) was not highly reproducible.…”