A one-pot Pd- and P450-catalyzed chemoenzymatic synthesis of a library of oxyfunctionalized biaryl alkanoic acids leveraging a substrate anchoring approach

Publication Date

8-1-2023

Document Type

Article

Publication Title

Journal of Inorganic Biochemistry

Volume

245

DOI

10.1016/j.jinorgbio.2023.112240

Abstract

A one-pot chemoenzymatic approach was developed by combining Palladium-catalysis with selective cytochrome P450 enzyme oxyfunctionalization. Various iodophenyl alkanoic acids could be coupled with alkylphenyl boronic acids to generate a series of alkyl substituted biarylalkanoic acids in overall high yield. The identity of the products could be confirmed by various analytical and chromatographic techniques. Addition of an engineered cytochrome P450 heme domain mutant with peroxygenase activity upon completion of the chemical reaction resulted in the selective oxyfunctionalization of those compounds, primarily at the benzylic position. Moreover, in order to increase the biocatalytic product conversion, a reversible substrate engineering approach was developed. This involves the coupling of a bulky amino acid such as L- phenylalanine or tryptophan, to the carboxylic acid moiety. The approach resulted in a 14 to 49% overall biocatalytic product conversion increase associated with a change in regioselectivity of hydroxylation towards less favored positions.

Funding Number

1807870

Funding Sponsor

National Science Foundation

Keywords

Biarylalkanoic acid, C-C bond formation and C–H oxyfunctionalization, Chemoenzymatic synthesis, Cross-coupling and biocatalysis, Cytochrome P450, Substrate engineering

Department

Research Foundation

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