Synthesis and absolute stereochemistry of (+)- and (–)-benz[a]anthracene 8,9-oxide and derived mammalian liver metabolites of benz[a]-anthracene

Abstract

Benz[a]anthracene 8,9-oxide, (5), a major initial metabolite of benz[a]anthracene, has been synthesised in optically pure form. The (–)-enantiomer has been unequivocally assigned as [8S,9R] by configurational correlation with (+)-trans-9S-bromo-8S-(menthyloxyacetoxy)-8,9,10,11-tetrahydrobenz[a]anthracene (1B) whose absolute stereochemistry has been determined by X-ray crystal-structure analysis. The major isolated mammalian liver metabolite of benz[a]anthracene, (–)-8,9-dihydroxy-8,9-dihydrobenz[a]-anthracene, (11), has [8R,9R] stereochemistry. It is deduced that the latter (–)-(8R,9R)-dihydrodiol is enzymatically derived from benz[a]anthracene (+)-(8R,9S)-oxide, and that it may be converted into trans-8R,9S-dihydroxy-10S,11R-epoxy-8,9,10,11-tetrahydrobenz[a]anthracene prior to being covalently bonded to cellular nucleic acids.