Chemoenzymatic Cascades toward Aliphatic Nitriles Starting from Biorenewable Feedstocks

Abstract

A modern concept of producing nitriles involves aldoxime dehydratases, which are capable of dehydrating aldoximes to the corresponding nitriles without need of a cofactor. Aldoximes as the starting material for nitrile synthesis are easily prepared by condensation of hydroxylamine with the corresponding aldehydes. In this contribution we present chemoenzymatic cascade reactions toward nitriles consisting of an initial nitroxyl radical-catalyzed oxidation of aliphatic alcohols to aldehydes using sodium hypochlorite as the oxidation agent, subsequent condensation of the aldehyde with hydroxylamine, and a biocatalytic dehydration using aldoxime dehydratases to the corresponding nitriles without isolation of intermediates and using the product nitrile as a solvent. These formal “solvent-free” cascades open up the possibility to use biorenewable sources, namely fatty acids, as the starting material for a chemoenzymatic nitrile synthesis. We were also able to apply this cascade concept for the synthesis of aliphatic dinitriles, which are used as, e.g., a precursor for polymer building blocks. Overall yields without isolation of intermediates of up to 70% with very simple product isolation were achieved.

Biocatalysis making waves in organic chemistry

“…Whole cell preparations have successfully been utilised in flow, demonstrating the versatility of these enzymes. [308][309][310] 2.3.2 Oxidation reactions 2.3.2.1 Alcohol oxidation to aldehydes. Enzyme-catalysed alcohol oxidation to aldehydes, relevant compounds for the flavour and fragrance industry, can be carried out by the classic nicotinamide-dependent alcohol dehydrogenases (ADHs).…”

Nitrile Synthesis with Aldoxime Dehydratases: A Biocatalytic Platform with Applications in Asymmetric Synthesis, Bulk Chemicals, and Biorefineries

“…This may provide improved environmental metrics due to the wastewater associated with the downstream when DMSO is removed [ 8 , 9 ]. In a more recent work, the concept has been further extended by starting with alcohols as biogenic raw materials and performing the ((2,2,6,6-Tetramethylpiperidin-1-yl)-oxyl) TEMPO-mediated oxidation, oxime formation, and biocatalytic step involving aldoxime dehydratases [ 33 ]. As in previous cases, a careful optimization of the multi-step approach was needed to secure that the different catalysts are not deactivated and that compatible conditions are found.…”

Chemoenzymatic one-pot reaction from carboxylic acid to nitrile via oxime

“…We previously reported that CAR biocatalysts retain their activity, when exposed to water-immiscible organic solvents like nheptane or biocompatible nhexadecane for ISPR, 26,27 but little was known about co-solvent effects of these solvents on Oxds. Previous studies with different Oxds reported on (di)nitrile products as second layer to achieve exceptional product titers in oxime dehydration reactions, 32 which hints towards organic solvent tolerance of Oxds. 32 To verify this assumption, immiscible organic solvents previously selected for aldehyde production 26 were examined as media in the oxime dehydration step.…”

“…Previous studies with different Oxds reported on (di)nitrile products as second layer to achieve exceptional product titers in oxime dehydration reactions, 32 which hints towards organic solvent tolerance of Oxds. 32 To verify this assumption, immiscible organic solvents previously selected for aldehyde production 26 were examined as media in the oxime dehydration step. At the same time, the robustness of OxdBr1 towards oxygen was assessed because the reactions were carried out in tubes with a large headspace of air.…”