Enzyme-Based Organic Synthesis. Cheanyeh Cheng

Enzyme-Based Organic Synthesis - Cheanyeh Cheng


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of activated double bond catalyzed by the OYE family has been investigated in great detail. The reaction proceeds in a two‐stage bi‐bi ping‐pong mechanism: the OYE flavin cofactor is first reduced at the expense of a nicotinamide cofactor NAD(P)H, which is followed by hydride transfer to the Cβ of the substrate (the reductive half reaction), whereas a tyrosine residue of the ER adds another proton to Cα of the double bond from the opposite side (the oxidative half reaction), with both reductive and oxidative substrates binding within the active site. This mechanism results in a trans addition of [2H] to the double bond of the substrate with absolute stereospecificity (Scheme 2.40).

Chemical reaction depicting asymmetric reduction of activated alkene substrates catalyzed by OYE enzymes.

      ERs used for asymmetric reduction of electronically activated C=C bonds, with a few exceptions, almost exclusively are isolated from Saccharomyces spp. yeasts, particularly, from the domesticated species S. cerevisiae. However, baker’s yeast just represents a small fraction within the vast yeast kingdom. Recently, Buzzini et al. carried out a screening on 23 so‐called nonconventional yeasts (NCYs) belonging to 21 species of the genera Candida, Cryptococcus, Debaryomyces, Hanseniaspora, Kazachstania, Kluyveromyces, Lindnera, Nakaseomyces, Vanderwaltozyma, and Wickerhamomyces for the whole‐cell bioreduction of α,β‐unsaturated ketones and aldehydes. Results show that extremely high yields (>90%) or even total bioconversion yields for the asymmetric reduction of the conjugated C=C bond of ketoisophorone (KIP) and 2‐methyl‐cyclopentanone (2‐MCPO) were catalyzed by ERs in a few NCYs. The catalytic efficiency of these NCYs declined for aldehydes [(S)‐(−)‐perillaldehyde ((S)‐PA) and α‐methyl‐cinnamaldehyde (MCA)]. The NCY whole cells were in lyophilized form and glucose was used for NAD(P)H cofactor recycling system [180].

      It was reported that indirectly regenerating YqjM or NemA (N‐ethylmaleimide reductase from E. coli) of reduced nicotinamide cofactors can be simplified by an efficient and convenient direct regeneration of catalytically active reduced flavins with the cell‐free bioreductions of activated conjugated C=C double bonds. In this process, reducing equivalents are provided via photocatalytic oxidation of a lot of simple sacrificial electron donors such as phosphite, formate, ethylenediaminetetraacetate (EDTA) [182]. Even when using crude cell extracts, the chemoselectivity of the photoenzymatic reduction was exclusive, only C=C double bond reduction without altering the ketone or aldehyde groups was observed. Up to 65% rates of the NADH‐driven reaction can be got while still preserving enantioselectivity.

Chemical reaction depicting asymmetric reduction of α-methylmaleic acid dimethylester with Z. mobilis or B. subtilis.

      A novel ER isolated from the bacterium Z. mobilis termed NCR reductase and OYEs 1–3 from yeast of Saccharomyces spp. were extended to use for the asymmetric reduction of a variety of activated C=C substrates. The activating groups in the investigated substrates include aldehyde, ketone, imide, nitro, carboxylic acid, and ester moieties. To control the stereospecificity of the reaction, strategies such as variation of the main substrate structure (cyclic vs. acylic), switching the (E/Z) configuration of the alkene moiety, modifying the substitution pattern (mono‐ vs. di‐, α‐ vs. β‐), or proper selection of the enzyme are utilized to allow the access to the opposite enantiomeric products. Results showed that reaction rates and stereoselectivities can be varied by different substrate type. The “substrate‐based stereocontrol” is related with the ring size of cycloalkenones, position of substituents on the C=C bond, and its E/Z configuration. The “enzyme‐based stereocontrol” was observed with nitroalkene in which the opposite enantiomeric products can be obtained by both NCR reductase and OYEs 1–3 [184].


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