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We describe the asymmetric synthesis of the most pleasant enantiomer of Jessemal fragrance. The key steps are (i) the one-pot reduction of an α-chloro-tetrasubstituted cyclohexenone to give the chlorohydrin, catalyzed by two stereoselective redox enzymes (an ene-reductase and an alcohol dehydrogenase); (ii) the regioselective epoxide ring-opening with organocuprate or organolithium nucleophiles. Density functional theory calculations together with the Curtin-Hammett principle allowed the rationalization of the regioselectivity.

The asymmetric hydrogenation of conjugated tetrasubstituted alkenes with transition-metal catalysts is a challenging reaction, especially for substrates bearing a halide substituent. We describe a two-step multienzymatic reduction of a series of α-halo β-alkyl tetrasubstituted cyclic enones, affording halohydrins with three contiguous stereogenic centers, in good yield and with a high stereoselectivity. The reduction is catalyzed by a stereospecific ene-reductase (OYE2-3 or NemA) and a highly enantioselective alcohol dehydrogenase (ADH). The use of two enantiodivergent ADHs allows the control of the diastereoselectivity. The absolute stereochemical configurations of the products have been determined from the analysis of single-crystal structures (Flack's parameter). The enantiomeric excess (ee) has been determined by derivatization of the products with (R) Mosher's acid. Lastly, we extended our methodology also to a nonhalogenated substrate: the α-methyl ketoisophorone was reduced by two distinct enantiodivergent ene-reductases (flavin mononucleotide- and F 420-dependent), affording each enantiomer of the saturated ketone with ee > 98%.