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In a paper just accepted by the ACS journal Organic Process Research & Development, researchers at the Biocatalysis group of the Van 't Hoff Institute for Molecular Sciences present the concept of using multienzyme cascades for the conversion of bio-based, renewable and low-cost substrates into high-value chiral products. As a proof of concept, they describe the conversion of L-phenylalanine into enantiomerically pure 1,2-amino alcohols with a very high yield and atom-efficiency, while generating very little waste products.

Image from the table of contents of the journal, depicting the research
Image: HIMS.

The research was carried out in collaboration with the group of Prof. Ulrich Schwaneberg at RTWH Aachen University. The publication will be part of the journal's Special Issue on "Biocatalysis: Improving Enzymatic Processes through Protein and Reaction Engineering".

Abstract

Enantiomerically pure 1,2-amino alcohols are important compounds due to their biological activities and wide applications in chemical synthesis. In this work, we present two multienzyme pathways for the conversion of L-phenylalanine into either 2-phenylglycinol or phenylethanolamine in the enantiomerically pure form.

Both pathways start with the two-pot sequential four-step conversion of L-phenylalanine into styrene via subsequent deamination, decarboxylation, enantioselective epoxidation, and enantioselective hydrolysis. For instance, after optimization, the multienzyme process could convert 507 mg of L-phenylalanine into (R)-1-phenyl-1,2-diol in an overall isolated yield of 75% and >99% ee. The opposite enantiomer, (S)-1-phenyl-1,2-diol, was also obtained in a 70% yield and 98−99% ee following the same approach. At this stage, two divergent routes were developed to convert the chiral diols into either 2-phenylglycinol or phenylethanolamine.

The former route consisted of a one-pot concurrent interconnected two-step cascade in which the diol intermediate was oxidized to 2-hydroxy-acetophenone by an alcohol dehydrogenase and then aminated by a transaminase to give enantiomerically pure 2-phenylglycinol. Notably, the addition of an alanine dehydrogenase enabled the connection of the two steps and made the overall process redox-self-sufficient. Thus, (S)-phenylglycinol was isolated in an 81% yield and >99.4% ee starting from ca. 100 mg of the diol intermediate.

The second route consisted of a one-pot concurrent two-step cascade in which the oxidative and reductive steps were not interconnected. In this case, the diol intermediate was oxidized to either (S)- or (R)-2-hydroxy-2-phenylacetaldehyde by an alcohol oxidase and then aminated by an amine dehydrogenase to give the enantiomerically pure phenylethanolamine. The addition of a formate dehydrogenase and sodium formate was required to provide the reducing equivalents for the reductive amination step. Thus, (R)-phenylethanolamine was isolated in a 92% yield and >99.9% ee starting from ca. 100 mg of the diol intermediate.

In summary, L-phenylalanine was converted into enantiomerically pure 2-phenylglycinol and phenylethanolamine in overall yields of 61% and 69%, respectively. This work exemplifies how linear and divergent enzyme cascades can enable the synthesis of high-value chiral molecules such as amino alcohols from a renewable material such as L-phenylalanine with high atom economy and improved sustainability.

Publication details

Maria L. Corrado, Tanja Knaus, Ulrich Schwaneberg, and Francesco G. Mutti: High-Yield Synthesis of Enantiopure 1,2-Amino Alcohols from 2 LPhenylalanine via Linear and Divergent Enzymatic Cascades. Organic Process Research & Development, Published online March 28, 2022. DOI: 10.1021/acs.oprd.1c00490

See also

Research group Biocatalysis