In recent years, a growing number of pharmaceuticals containing nitrile moiety has been reported or entered the market or clinical trials. However, traditional methods of nitrile synthesis do not often comply with the principles of green chemistry due to their stoichiometric nature, the need for elevated temperatures and pressures or the utilization of toxic cyanide compounds. By serendipity, we have discovered an unprecedented formation of nitriles from alcohols that is catalyzed by a galactose oxidase variant originated from Fusarium sp. (GOx), which was initially engineered for the oxidation of secondary aromatic alcohols. In contrast, we have observed the formation of nitriles from alcohol with ammonia acting as a nitrogen donor and molecular oxygen as final electron acceptor. In this work, we have optimized the reaction conditions for the nitrile formation, investigated the substrate scope and proved the catalytic role of GOx in the formation of nitriles (Figure 1). Interestingly, the utilization of GOx in form of cell free extract enabled significant improvement of performance. The optimized process permitted to achieve a higher TON (ca. 3300) under the following optimal conditions: ca. 2.55 μM GOxM3-5, 400 mM NH3/NH4+ at pH 9, 30 °C and under air at atmospheric pressure. Additionally, the substrate scope of the promiscuous reaction was elucidated and included: benzyl alcohols, pyridylmethanols and cinnamic alcohol. Finally, the applicability of the reaction in organic synthesis was exemplified in a 150 milligram-scale synthesis of 2’-fluorobenzonitrile starting from the related alcohol using GOx in form crude cell extract, which afforded quantitative conversion and 75% isolated yield. In conclusion, we have discovered a catalytic feature of GOxM3-5 that enables the first-ever single-enzyme transformation of alcohols to nitriles and constitutes a valuable addition to the currently available biocatalytic toolbox.

Biocatalytic synthesis of nitriles solely from alcohols, ammonia and air

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.