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 anO6-protected-2-fluoroinosine with 4-amino-1,2,5-trihydroxydecanal followed by periodate oxidation of the vicinal diol.3An improved synthesis of the amino triols has been developed. Thesynandantidiasteromers 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 OsO4and a tertiary amine oxide as the stoichiometric oxidant led to scrambling of stereochemistry at C4. The scrambling was not observed when t-butylhydroperoxide was used as the oxidant.
Vanderbilt Institute of Chemical Biology Synthesis Core, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Plamen P
PP
Christov
Edward K
EK
Hawkins
Nathan R
NR
Kett
Carmelo J
CJ
Rizzo
4-hydroxynonenal; DNA adducts; Henry Reaction; dihydroxylation