Synthesis of the lipid peroxidation product 4‐hydroxy‐2(E)‐nonenal with 13C stable isotope incorporation

The aim of this work was to synthesize ¹³C internal standards for the quantification of 4‐hydroxy‐2(E)‐nonenal (HNE), a lipid peroxidation product, and of the etheno‐adducts possibly formed by HNE damage to DNA nucleobases. We designed an eight‐step synthesis starting from ethyl 2‐bromoacetate and giving access to 4‐[(tetrahydro‐2H‐pyran‐2‐yl)oxy]‐2(E)‐nonenal. This compound is a precursor of HNE. The scheme was then used to produce the ¹³C precursor [1,2‐¹³C₂]‐4‐[(tetrahydro‐2H‐pyran‐2‐yl)oxy]‐2(E)‐nonenal. [1,2‐¹³C₂]‐HNE was obtained by acid deprotection. All the intermediary and final compounds were fully characterized by IR, HRMS, ¹H and ¹³C NMR. It is the first synthesis of HNE which enables the incorporation of two ¹³C labels at determined positions. Copyright © 2008 John Wiley & Sons, Ltd.