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11.3: Reduction Reactions

Last updated

Mar 16, 2021
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- 11.2: Formation of Carbon-Carbon Bonds
- 11.4: Enantioselective Oxidations

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The enantioselective reduction of C=X double bonds (X = O, NR, C) to C-XH single bonds plays a major role in asymmetric synthesis.

Reduction of Ketones

The enantioselective reduction of ketones represents an atom-economical approach towards optically active alcohols. The biocatalytic reduction of ketones is based on the use of an alcohol dehydrogenase (ADH) as a catalyst, and a cofactor as a reducing agent. For example, ADH from Leifsonia sp. catalyses the reduction of substituted acetophenone to give secondary alcohols with high enantioselectivity (Scheme $\PageIndex{1}$ ). In this process, 2-propanol acts as a reducing agent oxidizing into acetone.

The keto group of 2,5-diketo ester can be selectively reduced with excellent regio- and enantioselectivity using E. coli cells with overexpressed ADH from Lactobacillus brevis (Scheme $\PageIndex{2}$ ). In this process 2-propanol acts as a reducing agent oxidizing into acetone.

The reduction of a wide range of aliphatic and aromatic ketones can be accomplished employing R. ruber ADH to give the corresponding alcohols with excellent enantioselectivity in 2-propanol (Scheme $\PageIndex{7}$ ).

Whereas formate dehydrogenase (FDH) from C. boidinii catalyzes selectively the reduction of keto group of β -keto esters with high enantioselectivity. In this reaction, formate is oxidized into carbon dioxide (Scheme $\PageIndex{4}$ ).

The FDH-based whole-cell can be used for the reduction of ethyl 4-chloro-3-oxobutanoate with 99% ee (Scheme $\PageIndex{5}$ ).

The use of FDH from C. boidinii has limitation due to its inability to regenerate NADP⁺. This has been overcome by expanding the application range of FDH-based cofactor regeneration to NADP⁺ -dependent ADHs (Scheme $\PageIndex{6}$ ). This involves the integration of an additional enzymatic step within the cofactor-regeneration cycle that is exemplified in the reduction of acetophenone to (R)-phenylethanol. In this process, the pyridine nucleotide transhydrogenase (PNT)-catalyzes regeneration of NADPH from NADP⁺ under consumption of NADH forming NAD⁺.

Further, for recycling the cofactor NAD(P)H, the use of a glucose dehydrogenase (GDH) has been demonstrated. In this system, D-glucose is oxidized to D-gluconolactone, while the oxidized cofactor NAD(P⁺) is reduced to NAD(P)H. Since D-gluconolactone is then hydrolyzed into D-gluconic acid, the reaction is irreversible shifting the whole process towards the desired alcohol product formation. This GDH coupled cofactor-regeneration process has been used for the reduction of ketone to alcohol with high enantioselectivity (Scheme $\PageIndex{7}$ ).

This principle has been recently used for the reduction of ethyl 6-benzyloxy-3,5-dioxohexanoate to afford ethyl (3 R,5 S )-6-benzyloxy-3,5-dihydroxyhexanoate with 99% ee employing ADH from Acinetobacter calcoaceticus in combination with a GDH and glucose (Scheme $\PageIndex{8}$ ).

Reduction of Ketones

Recombinant whole-cell catalytic system having E. coli , co-expressing both the ADH from S. salmonicolor and the GDH from B. megaterium , has been developed for the asymmetric reduction of 4-chloro-3-oxobutanoate in a mixture of n -butyl acetate/water (Scheme $\PageIndex{9}$ ). It is an elegant approach toward tailor-made biocatalysts containing both of the desired enzymes, ADH and GDH, in overexpressed form (Scheme $\PageIndex{9}$ ).

The application of recombinant whole-cell biocatalytic system has been further demonstrated in pure aqueous media without the need of addition of external amount of cofactor (Scheme $\PageIndex{10}$ ). This method is economical and simple, and finds applications for the reduction of a wide range of ketones (Scheme $\PageIndex{10}$ ).

Reductive Amination of α -Keto Acids

Enzyme catalyzed asymmetric reductive amination of α -keto acids represents a straightforward method to access optically active α -amino acids. For example, L- tert- leucine, which serves as building block for the pharmaceutical industry, is obtained with high conversion and enantioselectivity using a leucine dehydrogenase for the reductive amination and an FDH from C.boidinii (Scheme $\PageIndex{11}$ ). The latter is required for an in situ recycling of the cofactor NADH.

Similarly, the synthesis of L-6-hydroxynorleucine can be accomplished from α -keto acid with complete conversion and >99% enantioselectivity (Scheme $\PageIndex{12}$ ). In this reaction, a beef liver glutamate dehydrogenase has been used as L-amino acid dehydrogenase and a GDH from B. megaterium has been used for the cofactor regeneration.

However, the need for the addition of expensive cofactor NAD⁺ as well as the isolation and cost of the enzymes make these approaches are limited. Thus, efforts have been made to address these aspects by employing a whole-cell catalyst, having both an amino acid dehydrogenase and FDH in overexpressed form. For example, the synthesis of L-allysine ethylene acetal has been shown using a whole-cell catalyst, Pichia pastoris cells having a phenylalanine dehydrogenase from Thermoactinomyces intermedius and an FDH from P. pastoris (Scheme $\PageIndex{13}$ ).

Reduction of Activated Carbon-Carbon Double Bonds

The reduction of carbon-carbon double bonds using the biocatalytic systems has high potential in organic chemistry. However, this process is less explored compared to the C=O reduction of ketones and keto esters. The reduction of the carbon-carbon double bond in ketoisophorone has been accomplished using whole-cell catalyst overexpressing an enolate reductase from Candida macedoniensis and a GDH (Scheme $\PageIndex{13}$ ). This study can be regarded as one of the pioneering works in the reduction of carbon-carbon double bonds using biocatalytic systems.

α,β -Unsaturated carboxylic acids can also be used as substrates. For example, α -chloroacrylic acid can be converted into α -chloropropionate using an enolate reductase from Burkholderia sp ., in high enantioselectivity (Scheme $\PageIndex{14}$ ).

Besides, enone and α,β -unsaturated carboxylic acid, nitroalkanes are also suitable substrates for enoate reductase. For example, the reduction of carbon-carbon double bond in Z -nitroalkenes proceed reaction to give 2-substituted 3-nitropropanoates with high conversion and in most cases with high enantioselectivity (Scheme $\PageIndex{15}$ ).

Transamination $\PageIndex{1}$

Depending on the nature of the transaminase, α -keto acids and ketones proceed reaction to give α-amino acids and amines with a stereogenic center in α -position, respectively. For example, a coupling of the transaminase process with an irreversible aspartate aminotransferase-catalyzed transamination process using cysteine sulfinic acid as an amino donor has been used for the synthesis of various types of non-natural 3- or 4-substituted glutamic acid analogues (Scheme $\PageIndex{16}$ ).

Furthermore, the highly efficient synthesis (S)-methoxyisopropylamine has been accomplished using a recombinant whole-cell catalyst overexpressing a transaminase. A key feature in this process is the high substrate concentration and the desired target molecule can be obtained with excellent enantioselectivity (Scheme $\PageIndex{17}$ ).

Reduction of Ketones

Reduction of Ketones

Reductive Amination of α -Keto Acids

Reduction of Activated Carbon-Carbon Double Bonds

Transamination11.3.1\PageIndex{1}

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Transamination $\PageIndex{1}$