Multienzymatic Stereoselective Reduction of Tetrasubstituted Cyclic Enones to Halohydrins with Three Contiguous Stereogenic Centers

Abstract

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%.

Enzymatic strategies for asymmetric synthesis

“…In a few published examples, the corresponding products were obtained with high diastereoselectivity (Scheme 6). 60,61 In both reported cases, the resulting products were further reduced by alcohol dehydrogenases, thereby granting access to -butyrolactones with two, and halohydrins with three contiguous stereocenters, respectively, with excellent ee and de values (>99%). Scheme 6.…”

“…Access to two (A) or three (B) chiral centers via bi-enzymatic reductive cascades in A) onepot two-step 60 and B) one-pot one-step. 61 A recycling system was used in both cases to regenerate NADPH (ADH-EVO270: commercial alcohol dehydrogenase, GDH: glucose dehydrogenase, Lk-ADH:…”

“…As recently demonstrated, these enzymes also proceed via a trans -addition of [2H] and could reduce tetrasubstituted cyclic enones with high stereo- and diastereoselectivity. 61 In selected cases, including the reduction of ketoisophorone and 3-methylcycloalk-2-enone, FDR appeared stereocomplementary to OYE1 ( Scheme 8 ). 74 …”

Ene‐Reductase: A Multifaceted Biocatalyst in Organic Synthesis

“…Asymmetric hydrogenation of tetrasubstituted alkenes using transition‐metal catalyst is challenging and demands high H 2 pressure and temperature. To overcome these harsh conditions, the Gatti group reported a new method using multienzyme biocatalysis to reduce tetra substituted cyclic enones [83] . According to their report the combination of OYE‐type ERs with Alcohol dehydrogenases in a cascade process allowed the one‐pot stereoselective formation of α ‐chlorohydrins/alcohol with three contiguous stereogenic centres (Scheme 7e), and a diol with four stereogenic centers (all in good yield and with high stereoselectivity).…”

“…(a) Ene-reductases and Keto-reductases catalysed synthesis of four stereoisomers of dihydrocarvone, [78] (b) Synthesis of alkyl-substituted γbutyrolactone using ER and ADH in one-pot cascade, [79] (c) Ene-reductase and Baeyer-Villiger Monooxygenase catalysed reductions of cinnamaldehyde to corresponding alcohol 2-Phenylethanol, [80] (d) ER-IRED catalysed synthesis of diastereomerically enriched amine heterocycles, [81] (e) One pot ER-ADH catalysed α-chlorohydrins/alcohol formation with three contiguous stereogenic centers. [83] the Turner group. [81] Several enzymes were examined, and among them, flavin-independent dehydrogenase NtDBR found to be the best.…”