A One‐Pot Biocatalytic Cascade to Access Diverse l ‐Phenylalanine Derivatives from Aldehydes or Carboxylic Acids

Anderson, Shelby R.; Gopal, Madan R.; Spangler, Abigail P.; Jones, Michaela A.; Wyllis, D'Jana R.; Kunjapur, Aditya M.

doi:10.1002/cctc.202401979

Title: A One‐Pot Biocatalytic Cascade to Access Diverse l ‐Phenylalanine Derivatives from Aldehydes or Carboxylic Acids

Journal Article · Fri Dec 27 00:00:00 UTC 2024 · ChemCatChem

DOI: https://doi.org/10.1002/cctc.202401979 · OSTI ID:2530243

^[1]; Gopal, Madan R. ^[1]; Spangler, Abigail P. ^[1]; Jones, Michaela A. ^[1]; Wyllis, D'Jana R. ^[1]; Kunjapur, Aditya M. ^[1]

Department of Chemical and Biomolecular Engineering University of Delaware 150 Academy St Newark Delaware 19716 USA

Abstract Nonstandard amino acids (nsAAs) that are l ‐phenylalanine derivatives with aryl ring functionalization have long been harnessed in natural product synthesis, therapeutic peptide synthesis, and diverse applications of genetic code expansion. Yet, to date, these chiral molecules have often been the products of poorly enantioselective and environmentally harsh organic synthesis routes. Here, we reveal the broad specificity of multiple natural pyridoxal 5′‐phosphate (PLP)‐dependent enzymes, specifically an l ‐threonine transaldolase, a phenylserine dehydratase, and an aminotransferase, toward substrates that contain aryl side chains with diverse substitutions. We exploit this tolerance to construct a one‐pot biocatalytic cascade that achieves high‐yield synthesis of 18 diverse l ‐phenylalanine derivatives from aldehydes under mild aqueous reaction conditions. We demonstrate the addition of a carboxylic acid reductase module to this cascade to enable the biosynthesis of l ‐phenylalanine derivatives from carboxylic acids that may be less expensive or less reactive than the corresponding aldehydes. Finally, we investigate the scalability of the cascade by developing a lysate‐based route for preparative‐scale synthesis of 4‐formyl‐ l ‐phenylalanine, a nsAA with a bio‐orthogonal handle that is not readily market‐accessible. Overall, this work offers an efficient, versatile, and scalable route with the potential to lower manufacturing costs and democratize synthesis for many valuable nsAAs.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2530243

Journal Information:: ChemCatChem, Journal Name: ChemCatChem Journal Issue: 5 Vol. 17; ISSN 1867-3880

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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