Synthesis of optically active trans-dihydrodiol and syn- and anti-diol epoxide metabolites of polycyclic aromatic hydrocarbons.

Abstract

The stereocontrolled syntheses of the optically active <italic> trans</italic>-9,10-dihydrodiol and <italic>syn</italic>- and <italic>anti </italic>-9,10-diol 11,12-epoxide metabolites of cocarcinogenic benzo[<italic> e</italic>]pyrene have been accomplished through the use of the aryne-furan cycloaddition methodology. The aryne precursor 4-bromo-5-tosyloxypyrene was obtained in 4 steps from pyrene, involving initial <italic>cis</italic>-dihydroxylation of pyrene using ruthenium(III) chloride (catalytic) and sodium periodate. The optical resolution was achieved efficiently by simple silica gel flash column chromatographic separation of a diastereomeric mixture of esters derived from optically pure (+)-(<italic>S</italic>)- a -methoxy-(phenyl)acetic acid and the racemic bromo-alcohol intermediate. In addition, benzo[<italic>e</italic>]pyrene, 9-hydroxybenzo[<italic>e</italic>]pyrene, <italic> trans</italic>-9,10-dihydrodiol and <italic>syn</italic>-9,10-diol 11,12-epoxide metabolites of triphenylene, which is an analog of benzo[<italic>e</italic>]pyrene, have been synthesized by a similar aryne-furan cycloaddition approach. Dimethyldioxirane epoxidation of <italic>trans</italic>-dihydrodiols of benzo[<italic>e</italic>]pyrene and triphenylene resulted in the highly stereoselective formation of the corresponding bay-region <italic>syn</italic>-diol epoxide. The initial effort on an asymmetric synthesis for PAH metabolites encountered difficulties after 3 steps into the synthetic sequence, which entailed a Diels-Alder reaction between 3,4-bis(benzyloxy)furan and a dienophile bearing chiral auxilliary, and a palladium-mediated coupling reaction. Specifically, the intermediate 5,6-dibenzyloxy-7-oxybicyclo[2.2.1]heptan-2-one, a bicyclic ketone, could not be transformed into the desired vinyl triflate. Alternative methods to circumvent this problem involved successfully converting the ketone into the vinyl alcohol or its hydrazones. Their subsequent transformation, i.e. vinyl alcohol to diene, or hydrazone to vinyl halide, could not be realized. Finally, a novel, efficient, generally applicable asymmetric route for the synthesis of <italic>trans</italic>-dihydrodiol metabolites of PAHs has been developed. The method involves the use of the Sharpless asymmetric dihydroxylation of an a , b -unsaturated ester and Grubbs' catalyst to effect ring closing metathesis of a divinyl diol precursor. This approach was employed in the synthesis of the enantiomerically pure <italic>trans</italic>-1,2-dihydrodiol metabolite of naphthalene, which was achieved in 9 steps and 18% overall yield from 2-bromobenzaldehyde. The <italic>trans</italic>-dihydrodiols can be converted stereoselectively into the corresponding <italic>syn</italic>- and <italic>anti</italic>-diol epoxide metabolites by the use of existing procedures.