Cascade enzymatic synthesis of a statin side chain precursor - the role of reaction engineering in process optimization.

Statins are an important class of drugs used to lower blood cholesterol levels and are often used to combat cardiovascular disease. In view of the importance of safe and reliable supply and production of statins in modern medicine and the global need for sustainable processes, various biocatalytic strategies for their synthesis have been investigated. In this work, a novel biocatalytic route to a statin side chain precursor was investigated in a one-pot cascade reaction starting from the protected alcohol -(3-hydroxypropyl)-2-phenylacetamide, which is oxidized to the corresponding aldehyde in the first reaction step, and then reacts with two equivalents of acetaldehyde to form the final product -(2-((2,4,6)-4,6-dihydroxytetrahydro-2-pyran-2-yl)ethyl)-2-phenylacetamide (phenylacetamide-lactol).

Biocatalytic Transamination of Aldolase-Derived 3-Hydroxy Ketones.

Although optical pure amino alcohols are in high demand due to their widespread applicability, they still remain challenging to synthesize, since commonly elaborated protection strategies are required. Here, a multi-enzymatic methodology is presented that circumvents this obstacle furnishing enantioenriched 1,3-amino alcohols out of commodity chemicals. A Type I aldolase forged the carbon backbone with an enantioenriched aldol motif, which was subsequently subjected to enzymatic transamination.

Biocatalytic Synthesis of Homochiral 2-Hydroxy-4-butyrolactone Derivatives by Tandem Aldol Addition and Carbonyl Reduction.

Chiral 2-hydroxy acids and 2-hydroxy-4-butyrolactone derivatives are structural motifs often found in fine and commodity chemicals. Here, we report a tandem biocatalytic stereodivergent route for the preparation of these compounds using three stereoselective aldolases and two stereocomplementary ketoreductases using simple and achiral starting materials. The strategy comprises (i) aldol addition reaction of 2-oxoacids to aldehydes using two aldolases from , 3-methyl-2-oxobutanoate hydroxymethyltransferase (KPHMT ), 2-keto-3-deoxy-l-rhamnonate aldolase (YfaU ), and --hydroxybenzylidene pyruvate hydratase-aldolase from (HBPA ) and (ii) subsequent 2-oxogroup reduction of the aldol adduct by ketopantoate reductase from (KPR ) and a Δ-piperidine-2-carboxylate/Δ-pyrroline-2-carboxylate reductase from pv.

Three-Component Stereoselective Enzymatic Synthesis of Amino-Diols and Amino-Polyols.

Amino-polyols represent attractive chemical building blocks but can be challenging to synthesize because of the high density of asymmetric functionalities and the need for extensive protecting-group strategies. Here we present a three-component strategy for the stereoselective enzymatic synthesis of amino-diols and amino-polyols using a diverse set of prochiral aldehydes, hydroxy ketones, and amines as starting materials. We were able to combine biocatalytic aldol reactions, using variants of d-fructose-6-phosphate aldolase (FSA), with reductive aminations catalyzed by IRED-259, identified from a metagenomic library.