Chemoselective Biohydrogenation of Alkenes in the Presence of Alkynes for the Homologation of 2‐Alkynals/3‐Alkyn‐2‐ones into 4‐Alkynals/Alkynols

Abstract

The chemoselective hydrogenation of alkenes in the presence of alkynes is a very challenging transformation to achieve with traditional chemical methods. The development of an effective procedure to perform this transformation would enrich the tool-kit available to organic chemists for the development of useful synthetic routes, and the creation of novel structural motifs. The reduction of activated alkene bonds by ene-reductases (ERs) is completely chemoselective, because of the mechanism of the reaction. Thus, we investigated the use of ERs belonging to the Old Yellow Enzyme family for the reduction of α,β-unsaturated aldehydes with a conjugated C�C triple bond at the γ position. This reaction was exploited as the key step for the development of an effective homologation route to convert aryl and alkyl substituted propynals and butynones into 4-alkynals and 4-alkynols, avoiding some troublesome or hazardous steps of known synthetic routes. Scheme 4. Conversion of aldehydes (R)-8 a, b and alcohols (S)-10 a, b into derivatives of known absolute configuration.

Catalytic Asymmetric Conjugate Reduction

“…The opposite enantiomeric product was obtained with OYE2 from Saccharomyces cerevisiae and EBP1 from Candida albicans with 96 % ee (not shown) [187, 192, 193, 199, 200] . More recently, Brenna and co‐workers showed that β‐alkynyl enals are also suitable substrates for OYE3 when paired with alcohol dehydrogenase EVO200 in a cascade double reduction to chiral alcohols [201] . This process was found to be efficient mostly for the formation of α‐stereocenters (Figure 39).…”

Ene‐Reductase: A Multifaceted Biocatalyst in Organic Synthesis

“…also helped to get an excellent yield of cyclized product. The application of the ene‐reductases from Old Yellow Enzymes for the asymmetric and chemoselective reduction of unsaturated compounds were further strengthened by Tentori and co‐workers in their chemoselective reduction of alkenes in presence of alkynes [50] . The α , β ‐unsaturated aldehydes with a conjugated triple bond at the γ ‐position were selectively reduced to homologous alkynyl products (Scheme 3c) which traditionally required harsh and/or metal‐catalysed reaction conditions [51–53] .…”

“…The application of the ene-reductases from Old Yellow Enzymes for the asymmetric and chemoselective reduction of unsaturated compounds were further strengthened by Tentori and coworkers in their chemoselective reduction of alkenes in presence of alkynes. [50] The α,β-unsaturated aldehydes with a conjugated triple bond at the γ-position were selectively reduced to homologous alkynyl products (Scheme 3c) which traditionally required harsh and/or metal-catalysed reaction conditions. [51][52][53] The classical synthetic modification of (R)carvone to the reduced (2R,5R)-dihydrocarvone asymmetrically was devised by Paul and co-workers, [54] employing an enereductase FOYE-1, obtained from an acidophilic iron oxidizer OYE.…”

“…The results Scheme 3. (a) Reduction of β-activated vinylphosphonates, [47] (b) ER-mediated reductive carbocyclization of α,β-unsaturated aldehydes and ketones, [49] (c) Chemoselective reduction of alkenes in presence of alkynes, [50] (d) Biocatalytic reduction of oximes to an amine, [55[ (e) Proposed reaction pathway of conversion from β-keto-α-oximo ester to tetrasubstituted pyrazine, (f) One-pot biosynthesis of α-substituted β-ketoesters using enereductase (NerA), [57] (g) Reductions of less activated C=C bond of aromaticand aliphatic-substituted acrylic acids by ER 36 enzyme. [58] Chemistry-A European Journal showed changing the ester moiety from ethyl to bigger groups such as benzyl offered good conversion (except XenA), but bulkier substituents in the keto resulted in lower yield.…”

Ene‐Reductase Catalyzed Regio‐ and Stereoselective 1,4‐Mono‐Reduction of Pseudoionone to Geranylacetone

“…Despite the many papers published, studies describing the mono‐reduction of conjugated double bonds in a regioselective fashion are scarce. Only five reports can be found in literature: namely (i) the use of Penicillium citrinum hyphae in a biphasic system; [9] (ii) whole‐cell biocatalysis with Rhodotorula mucilaginosa used as submerged culture; [10] (iii) the utilization of F420‐dependent reductases (FDRs); [11] and EREDs belonging either (iv) to the MDR‐superfamily like the ones from the fungus Cyclocybe aegerita [12] or (v) the Old Yellow Enzyme (OYE) family [13] . Among these, the first four describe the regioselective 1,4‐reduction in a α,β,γ,δ‐double bond conjugated system, while the fifth one showed the chemoselective reduction of α,β‐unsaturated aldehydes with a conjugated C≡C triple bond at the γ position.…”