SYNTHESIS OF HIGHER OXIDIZED METABOLITES OF DIBENZ[A,J]ANTHRACENE IMPLICATED IN THE MECHANISM OF CARCINOGENESIS

Higher oxidized metabolites are implicated as active carcinogenic form s of polycyclic aromatic hydrocarbons which have two or more bay or fj ord molecular regions, such as dibenz[a,j]anthracene. These include th e bis(dihydrodiols) and phenolic dihydrodiols which may potentially un dergo further metabolism to the corresponding diol epoxides. The latte r react with DNA resulting in mutations that lead to tumorigenesis. Pr ior characterization of these metabolites has been based largely on HP LC and spectroscopic evidence. This paper reports efficient syntheses of the trans-trans-3,4,8,9-dihydrodiol (1) and the 10- and Il-phenolic trans-3,4-dihydrodiols of dibenz[a,j]anthracene (3a,b). The synthetic route to 1 entails as the key steps asymmetric dihydroxylation of an appropriately substituted stilbene precursor employing a Sharpless cat alyst followed by intramolecular cyclodehydrobromination catalyzed by Pd(PPh3)(2)Cl-2. The syntheses of 3a,b proceed via sequences involving a Wittig reaction of anisaldehyde with a phosphonium salt of 2-chloro -3-methylbenzyl bromide to give a stilbene compound and then photocycl ization, conversion of the product to a phosphonium salt, a second Wit tig reaction and photocyclization, reductive dechlorination, and conve rsion of the resulting trimethoxydibenz[a,j] anthracenes to the phenol ic dihydro diols. A key feature of these syntheses is the effective us e of chloro substituents to block photocyclization in an undesired dir ection. These methods are potentially applicable to the synthesis of a nalogous higher oxidized metabolites of other polycyclic aromatic carc inogens.