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• Biosynthesis of vanillin using EUGO is optimised. • The best conditions allow an organic solvent free process of 9.9 g prod L−1 h−1. • Immobilised EUGO allowed the biocatalyst to be reused up to 18 reaction cycles. • Optimised conditions increased the safety and reduced the environmental impact. Vanilla is the second most expensive spice in the world. This issue triggered the necessity to obtain its flavour compound, vanillin, by alternative methods, most of which have focused on biosynthesis since it can be labelled as "natural" and sold at higher price. In this work, a process for the enzymatic synthesis of vanillin has been optimised, not only from a process metrics point of view but also from an environmentally sustainable perspective. The maximum biocatalyst activity and stability was taken into account for the selection of the reaction conditions. Soluble and immobilised eugenol oxidase (EUGO) was tested under both reaction conditions. The optimum conditions obtained lead to an organic solvent free process reaching 9.9 g prod L−1 h−1. Moreover, the use of immobilised EUGO allowed the biocatalyst to be reused up to 18 reaction cycles, improving the biocatalyst yield more than 12-fold, thus also reducing the biocatalyst associated cost. [ABSTRACT FROM AUTHOR]

• Development of an enzymatic synthesis of a statin precursor. • Process optimization by Design of Experiments. • Enzyme immobilisation improved the stability of alcohol dehydrogenase. • The immobilised derivative could be re-used in several reaction cycles. Statins inhibit the synthesis of LDL-cholesterol which is related to cardiovascular diseases. One of the key steps in the synthesis of the chiral side chain of some statins is the oxidation of the chlorolactol to chlorolactone. This oxidation has been performed by an alcohol dehydrogenase (ADH99) using a NADPH-oxidase (NOX) as a cofactor regeneration system. The reaction conditions were optimised obtaining high reaction yield (94.7 %), space time yield (4.6 g L−1 h−1) and biocatalyst yield (7.9 mg product mg−1 biocatalyst). Both enzymes have been efficiently immobilised onto different supports (Eupergit® CM, Amino-agarose, Epoxy agarose-UAB, Purolite ECR8409 and ECR8415). ADH99 showed a stability improvement when immobilised. However, NOX did not show any significant stability enhancement. The most stable ADH99 immobilised derivative, ADH99-Epoxy agarose-UAB, was used to perform the oxidation, improving 1.5-fold both, the total amount of product produced and the biocatalyst yield compared to the ADH99 soluble form. [ABSTRACT FROM AUTHOR]

• A new biocatalytic process for natural vanillin synthesis catalyzed by an eugenol oxidase is presented. • EUGO immobilised onto Epoxy-agarose-UAB was re-used up to 5 cycles showing a conversion higher than 80% and a yield higher than 50% in the last cycle. • The biocatalyst yield was improved more than 2-fold compared to the soluble enzyme. • This bioprocess offers an efficient method of producing natural vanillin which could compete with chemical methods that supply the market. Vanillin is one of the most important flavours produced in the world. Due to its increasing value and its demand, mainly in the food industry, several ways to obtain it at lower prices are under study. One of the routes is based on the oxidation of vanillyl alcohol by Eugenol oxidase (EUGO), which has high potential to be used at industrial scale owing to the high space time yields that can be obtained at lab scale (2.9 g L−1 h−1 of vanillin). Additionally, EUGO can be immobilised efficiently onto different supports (MANA-agarose, Epoxy-agarose and Purolite 8204F) which can be reused several times to perform the oxidation preserving good stability and improving more than 3-fold the biocatalyst yield. [ABSTRACT FROM AUTHOR]

N‐Functionalized amino acids are important building blocks for the preparation of diverse bioactive molecules, including peptides. The development of sustainable manufacturing routes to chiral N‐alkylated amino acids remains a significant challenge in the pharmaceutical and fine‐chemical industries. Herein we report the discovery of a structurally diverse panel of biocatalysts which catalyze the asymmetric synthesis of N‐alkyl amino acids through the reductive coupling of ketones and amines. Reactions have been performed on a gram scale to yield optically pure N‐alkyl‐functionalized products in high yields. [ABSTRACT FROM AUTHOR]

N‐Functionalized amino acids are important building blocks for the preparation of diverse bioactive molecules, including peptides. The development of sustainable manufacturing routes to chiral N‐alkylated amino acids remains a significant challenge in the pharmaceutical and fine‐chemical industries. Herein we report the discovery of a structurally diverse panel of biocatalysts which catalyze the asymmetric synthesis of N‐alkyl amino acids through the reductive coupling of ketones and amines. Reactions have been performed on a gram scale to yield optically pure N‐alkyl‐functionalized products in high yields. Reductive amination space exploration: A new family of biocatalysts has been characterized for the asymmetric synthesis of N‐functionalized amino acids (see scheme), which are important building blocks for the preparation of bioactive molecules, including peptides. The structurally diverse biocatalysts catalyzed the reductive coupling of ketones and amines on a gram scale to yield the optically pure N‐alkyl‐functionalized products in high yields. [ABSTRACT FROM AUTHOR]

Highlights • The N -alkyl amino acid moiety is widespread in Nature. • A number of commercial products related to health contain the N -alkylated amino acid moiety. • Biocatalysis provides efficient and sustainable methods of accessing the N -alkyl amino acid moiety. • N -methyl transferases and dehydrogenases can be used for the synthesis of N -alkyl amino acids. Abstract N -Alkylated-α-amino acids are useful building blocks for the pharmaceutical and fine chemical industries. Enantioselective methods of N -alkylated-α-amino acid synthesis are therefore highly valuable and widely investigated. While there are a variety of chemical methods for their synthesis, they often employ stoichiometric quantities of hazardous reagents such as pyrophoric metal hydrides or genotoxic alkylating agents, whereas biocatalytic routes can provide a greener and cleaner alternative to existing methods. This review highlights the occurrence of the N -alkyl-α-amino acid motif and its role in nature, important applications towards human health and biocatalytic methods of preparation. Several enzyme classes that can be used to access chiral N -alkylated-α-amino acids and their substrate selectivities are detailed. [ABSTRACT FROM AUTHOR]

Abstract: Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides. [ABSTRACT FROM AUTHOR]

Abstract: Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides. [ABSTRACT FROM AUTHOR]

A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzothiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)2BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield. [ABSTRACT FROM AUTHOR]

Abstract: Proof-of-concept has been demonstrated for the biocatalytic transformation of aciclovir into valaciclovir, attaining high conversions from a solid-to-solid biotransformation in l-valine methyl ester using various formulations of Subtilisin Carlsberg activated for use in organic solvent. [ABSTRACT FROM AUTHOR]

Abstract: The efficient synthesis of an α-trifluoromethyl-α-tosyloxymethyl epoxide is reported. This highly versatile building block may be reacted sequentially with two different nucleophiles to furnish α-trifluoromethyl tertiary alcohols. Furthermore, the two enantiomers of this key intermediate have been separated using chiral HPLC and the stereochemistry shown to be conserved during subsequent chemical manipulations. Finally, an enzyme-driven desymmetrisation approach has been successfully employed to confer chirality on an intermediate in the sequence. [Copyright &y& Elsevier]

The article presents chemical equation related to the article "Enzymatic- and Iridium-Catalyzed Asymmetric Synthesis of a Benzothiazepinylphosphonate Bile Acid Transporter Inhibitor" by D.J. Cowan and others, published in the periodical "Journal of Organic Chemistry" in 2013.