Enzyme-Based Organic Synthesis. Cheanyeh Cheng

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Scheme 2.39 Asymmetric reduction of ketones and polymerization of the optically pure monomers for application in material chemistry.

      2.2.2 Reduction of C═C Bonds

The asymmetric bioreduction of activated C=C bonds with the generation of up to two stereogenic centers is one of the most widely employed synthetic strategies for producing chiral molecules [171, 172]. Enoate reductases (ERs), NAD(P)H‐dependent flavin mononucleotide (FMN)‐containing oxidoreductases from the “Old Yellow Enzyme (OYE)” family (E.C. 1.6.99.1) [171, 173], are widely distributed in microorganisms such as bacteria [174], yeast [175], and filamentous fungi [176] and in higher plants [177] and stereoselectively catalyze the reduction of activated C=C bonds containing electron‐withdrawing groups (EWG) such as α,β‐unsaturated ketones, aldehydes, nitroalkenes, carboxylic acids, and derivatives (ester, anhydride, lactone, and cyclic imide), thus, affording the production of fine chemicals, pharmaceuticals, and agrochemical intermediates. Note that EWGs such as halogen, oxime, sulfoxide, or sulfone usually enhance the reaction rates but are not sufficient to activate a C=C bond alone [178]. The overall stereoselective reduction 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 C_β of the substrate (the reductive half reaction), whereas a tyrosine residue of the ER adds another proton to C_α 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).

In the past, the complexity of cofactor recycling has made the majority of the asymmetric reduction of activated C=C performed using whole fermenting cells, mostly baker’s yeast and anaerobic bacteria. For example, whole cell of baker’s yeast (S. cerevisiae) has been broadly used for the stereospecific reduction of many compounds containing activated carbon‐carbon double bond such as monoterpenes and sesquiterpenoids [179]. Since terpenes and terpenoids exhibit a wide variety of pleasant and floral scents, these properties make them extensively used in the perfumery and food industries. Monoterpenes and sesquiterpenoids, the chief components of the essential oils, not only act as precursors for new flavor derivatives but also are important building blocks for the preparation of new biologically active natural product drugs.