The Use of Directing Groups Enables the Selective and Efficient Biocatalytic Oxidation of Unactivated Adamantyl C‐H Bonds. Issue 21 (21st December 2016)

• Record Type: Journal Article
• Authors: Sarkar, Md. Raihan; Hall, Emma A.; Dasgupta, Samrat; Bell, Stephen G.
• Is Part Of: ChemistrySelect. Volume 1:Issue 21(2016)
• Page Start: 6700
• Page End: 6707
• Publication Date: 2016-12-21
• Subjects: C−H bond oxidation -- cytochrome P450 monooxygenases -- enzyme catalysis -- hydroxylation -- regioselectivity; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201601615
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: Adamantane, 1‐ and 2‐adamantanol and 2‐adamantanone, were poor substrates for the cytochrome P450 enzyme CYP101B1. The CYP101B1 catalysed oxidation of 1‐adamantyl methyl ketone, and methyl 2‐(1‐adamantyl acetate), were more active generating a majority of the 4‐hydroxy metabolite. Substrate engineering using acetate and isobutyrate ester directing groups significantly increased the affinity, activity and coupling efficiency of CYP101B1 for the esters compared to the parent adamantanols, resulting in enhanced product formation rates (720 to 1350 nmol.(nmol‐P450) −1 .min −1 ). The majority of the turnovers were selective for C−H bond hydroxylation with 4‐hydroxy‐1‐adamantyl isobutyrate and the 5‐hydroxy‐2‐adamantyl esters being generated as the sole majority product, 97 %, with high total turnover numbers, ranging from 4130 to 16500. In addition N‐(1‐adamantyl)acetamide, was oxidised by CYP101B1 whereas 1‐adamantylamine, was not. Whole‐cell biocatalytic reactions were used to generate the products in good yield. Overall the use of ester protecting groups and the modification of the amine to an amide enabled the more efficient and selective biocatalytic oxidation of adamantane frameworks. Abstract : The selective biocatalytic oxidation of the unactivated C−H bonds in adamantanols and an amine analogue was achieved by modification of the substrate using ester and amide directing groups. This approach improved the binding affinity, activity and selectivity of product formation enabling the efficient generation of the hydroxylated metabolites using a monooxygase enzyme.