Regiospecificity of peroxyl radical addition to (E)-retinoic acid.
The regiochemistry of peroxyl radical addition to (E)-retinoic acid (RA) was investigated. Peroxyl radicals, generated by reaction of 13-hydroperoxy-(9Z,11E)-octadecadienoic acid with hydroxo(porphyrinato)iron(III) in Tween 20 micelles, were reacted with RA. The major, and virtually exclusive, RA oxidation product was 5,6-epoxy-RA which was identified on the basis of cochromatography with the synthetic synthetic oxirane (in a reverse phase HPLC system), electronic absorption spectroscopy, high-field 1H-NMR, and EI mass spectrometry. These results suggest that peroxyl radicals react with RA by regioselective addition to either C5 or C6 yielding an endocyclic tertiary allylic or tertiary carbon-centered radical adduct, respectively. Subsequent beta-elimination of an alkoxyl radical yields the oxirane. Computational studies were carried out in order to gain mechanistic insights into the observed regiospecificity of the peroxyl radical-dependent epoxidation reaction; molecular mechanics and semiempirical quantum mechanical calculations were carried out using Tripos force field parameters and AM1, respectively. The results suggest that the regiospecific epoxidation may be influenced by the 5,6-olefinic function behaving as a partially-isolated double bond as well as inherent allylic A1,2 strain in the substituted cyclohexene ring as a consequence of substitutions at C1 and C6. In addition, calculated heats of formation indicated preferential peroxyl radical addition to C5 versus C6; this may reflect differences in the geometries of sp2-orbitals containing the radical densities rather than resonance contributions by the highly conjugated polyene system.
Samokyszyn
V M
VM
Department of Pharmacology & Toxicology (Division of Taxicology), University of Arkansas for Medical Sciences, Little Rock 72205, USA. victors@biomed.uams.edu
Freyaldenhoven
M A
MA
Chang
H C
HC
Freeman
J P
JP
Compadre
R L
RL
D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010545:Peroxides / Q000737:chemistry*; D014212:Tretinoin / Q000737:chemistry*
D010545:Peroxides; C049375:perhydroxyl radical; D014212:Tretinoin