Simplified synthesis of individual stereoisomers of the 4-hydroxynonenal adducts of deoxyguanosine

We previously reported the synthesis of the 1,N2-deoxyguanosine adducts of 4-hydroxynonenal, an important product of lipid peroxidation, which involved the nucleophilic aromatic substitution reaction of O6-protected-2-fluoroinosine with 4-amino-1,2,5-trihydroxydecanal followed by periodate oxidation of the vicinal diol.6 An improved synthesis of the amino triols has been developed. The syn and anti diastereomers of a key intermediate, 4-nitro-5-hydroxy-1-decene, were synthesized by a Henry reaction and separated; each diastereomer was further separated into individual enantiomers by chiral supercritical fluid chromatography. Of note, dihydroxylation of the terminal olefin under conventional conditions with catalytic OsO4 and a tertiary amine oxide as the stoichiometric oxidant led to scrambling of stereochemistry of the nitro group. The scrambling was not observed when t-butylhydroperoxide was used as the oxidant.