Issue 15, 2017

Towards the biodegradation pathway of fosfomycin

Abstract

Three functionalised propylphosphonic acids were synthesised to study C–P bond cleavage in R. huakuii PMY1. (R)-1-Hydroxy-2-oxopropylphosphonic acid [(R)-5] was prepared by chiral resolution of (±)-dimethyl 1-hydroxy-2-methylallyllphosphonate [(±)-12], followed by ozonolysis and deprotection. The N-(L-alanyl)-substituted (1R,2R)-2-amino-1-hydroxypropylphosphonic acid 10, a potential precursor for 2-oxopropylphosphonic acid (5) in cells, was obtained by coupling the aminophosphonic acid with benzotriazole-activated Z-L-alanine and hydrogenolytic deprotection. (1R*,2R*)-1,2-Dihydroxy-3,3,3-trifluoropropylphosphonic acid, a potential inhibitor of C–P bond cleavage after conversion into its 2-oxo derivative in the cell, was accessed from trifluoroacetaldehyde hydrate via hydroxypropanenitrile 21, which was silylated and reduced to the aldehyde (±)-23. Diastereoselective addition of diethyl trimethylsilyl phosphite furnished diastereomeric α-siloxyphosphonates. The less polar one was converted to the desired racemic phosphonic acid (±)-(1R*,2R*)-9 as its ammonium salt.

Graphical abstract: Towards the biodegradation pathway of fosfomycin

Supplementary files

Article information

Article type
Paper
Submitted
06 mar 2017
Accepted
21 mar 2017
First published
21 mar 2017
This article is Open Access
Creative Commons BY-NC license

Org. Biomol. Chem., 2017,15, 3276-3285

Towards the biodegradation pathway of fosfomycin

K. Pallitsch, A. Schweifer, A. Roller and F. Hammerschmidt, Org. Biomol. Chem., 2017, 15, 3276 DOI: 10.1039/C7OB00546F

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