Enzymatic esterification of lactones in aqueous buffer

Opening lactones with alcohols to yield esters can traditionally be achieved by acid or base catalysis. The produced esters are intermediates for a vast variety of reactions [1] and can also be used for polymerization reactions like for polycaprolactone. Recently a biocatalytic cascade was reported for the transformation of cyclohexanol to the nylon-6 monomer [2]. A key step was the in-situ capping strategy of the carboxylic functionality by opening ε-caprolactone (1a) with methanol to methyl-6-hydroxyhexanoate (1b) employing a crude preparation of horse liver esterase (HLE). The conversion was performed in aqueous buffer in the presence of 10% v/v methanol. Please click Additional Files below to see the full abstract

Cobalamin dependent methylation and demethylation by veratrol O-demethylase

The formation and breakage of C-O ether bonds are valuable synthetic transformations contributing to the structural diversification of natural products and pharmaceuticals [1-3]. Moreover, O-methylated phenol derivatives are useful building blocks for the manufacture of antioxidants, flavoring agents, fragrances, dyes, agrochemicals and fine chemicals [4,5]. Despite the large variety of chemical reactions for methylation and demethylation, none reaction is reversible and sustainable. They often lack chemo-, regio- and stereoselectivity and rely on harsh reaction conditions [6]. Thus, the development of milder alternatives such as biocatalytic methylation and demethylation reactions is of high interest [7]. Please click Additional Files below to see the full abstract

Biocatalytical access to amides

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Controlling stereoselectivity by enzymatic and chemical means to access enantiomerically pure (1S,3R)-1-benzyl-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline derivatives

A chemoenzymatic strategy for the synthesis of enantiomerically pure novel alkaloids (1S,3R)- 1-benzyl-2,3-dimethyl-1,2,3,4-tetrahydroisoquinolines is presented. The key steps are the biocatalytic stereoselective reductive amination of substituted 1-phenylpropan-2-one derivatives to yield chiral amines employing microbial x-transaminases, and the diastereoselective reduction of a Bischler– Napieralski imine intermediate by catalytic hydrogenation in the presence of palladium on charcoal, leading exclusively to the desired cis-isomerFil: Orden, Alejandro Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina;Fil: Schrittwieser, Joerg H.. University of Graz. Department of Chemistry, Organic and Bioorganic Chemistry; Austria;Fil: Resch, Verena. University of Graz. Department of Chemistry, Organic and Bioorganic Chemistry; Austria;Fil: Mutti, Francesco G.. University of Graz. Department of Chemistry, Organic and Bioorganic Chemistry; Austria;Fil: Kroutil, Wolfgang. University of Graz. Department of Chemistry, Organic and Bioorganic Chemistry; Austria

Broadening the substrate scope of strictosidine synthases by site-directed mutagenesis

The condensation of ß-arylethylamines with carbonyl compounds (Pictet-Spengler reaction) is employed in the synthesis of tetrahydro-β-carboline and isoquinoline scaffolds which are common motifs in many naturally occurring alkaloids. These compounds exhibit a range of biological activities and are thus interesting targets for organic synthesis and medicinal chemistry. Nature’s equivalent to the Pictet-Spengler reaction is catalyzed by the so called Pictet-Spenglerases. Within this class of enzymes, strictosidine synthases (STRs, EC 4.3.3.2) have attracted attention [1-4]. These enzymes catalyse the formation of the 1,2,3,4-tetrahydro-β-carboline (S)-strictosidine, a key intermediate in the monoterpenoid indole alkaloid biosynthetic pathway in higher plants. Please click Additional Files below to see the full abstract

Stereoselective synthesis of γ-hydroxynorvaline through combination of organo- and biocatalysis

An efficient route for the synthesis of all four diastereomers of PMP-protected α-amino-γ-butyrolacton to access γ-hydroxynorvaline was established. The asymmetric key steps comprise an organocatalytic Mannich reaction and an enzymatic ketone reduction. Three reaction steps could be integrated in a one-pot process, using 2-PrOH both as solvent and as reducing agent. The sequential construction of stereogenic centres gave access to each of the four stereoisomers in high yield and with excellent stereocontrol

Inverted binding of non-natural substrates in strictosidine synthase leads to a switch of stereochemical outcome in enzyme-catalyzed Pictet-Spengler reactions

The Pictet-Spengler reaction is a valuable route to 1,2,3,4-tetrahydro-Β-carboline (THBC) and isoquinoline scaffolds found in many important pharmaceuticals. Strictosidine synthase (STR), catalyzes the Pictet-Spengler condensation of tryptamine and the aldehyde secologanin to give (S)-strictosidine as a key intermediate in indole alkaloid biosynthesis. STRs also accept shortchain aliphatic aldehydes to give enantioenriched alkaloid products with up to 99% e.e. STRs are thus valuable asymmetric organocatalysts for applications in organic synthesis. The STR catalysis of reactions of small aldehydes gives an unexpected switch in stereopreference, leading to formation of the (R)-products. Here we report a rationale for the formation of the (R)-configured products by the STR enzyme from Ophiorrhiza pumila (OpSTR) using a combination of X-ray crystallography, mutational and molecular dynamics (MD) studies. We discovered that short chain aldehydes bind in an inverted fashion compared to secologanin leading to the inverted stereopreference for the observed (R)-product in those cases. The study demonstrates that the same catalyst can have two different productive binding modes for one substrate – but give different absolute configuration of the products by binding the aldehyde substrate differently. These results will guide future engineering of STRs and related enzymes for biocatalytic applications