Synthesis of optically active putative metabolites of carcinogenic polycyclic aromatic hydrocarbons.

Abstract

A general method for the synthesis of optically active diol epoxide metabolites of carcinogenic polycyclic aromatic hydrocarbons has been developed. The optical resolution of intermediary bromo alcohols, formed in the "aryne-furan" approach to the synthesis of active metabolites of polycyclic aromatic hydrocarbons (PAHs), has been systematically studied. The bromo alcohol intermediates were esterified using an optically pure chiral carboxylic acid, (+)-(S)-O-methylmandelic acid ((+)-MMA), and the resulting diastereomeric esters were readily separated by silica gel flash column chromatography. These separated diastereomers serve as precursors to the optically active diol epoxide metabolites. A highly stereo- and regioselective synthesis of optically pure enantiomers of anti-benzo (a) pyrene diol epoxide has been achieved. A crucial step involving ether-bridge opening of 8$\alpha$, 9$\alpha$-carbonyldioxy-7$\beta$, 10$\beta$-epoxy-7,8,9,10-tetrahydrobenzo (a) pyrene with boron tribromide was complicated by an unforeseen epimerization of the desired, initially produced bromo compound. However, use of boron trichloride afforded the corresponding chloro derivative with high stereo- and regiocontrol. Furthermore, similar synthetic strategies have been extended to triphenylene (TP) and 7,12-dimethylbenz (a) anthracene (7,12-DMBA) systems. In the TP system, (+)-(S)-MMA esters of 1$\beta$-bromo-2$\alpha$, 3$\alpha$-diacetoxy-4$\beta$-hydroxy-1,2,3,4-tetrahydrotriphenylene were found to be unseparable by silica gel chromatography. After replacement of the diacetate protecting groups with a cyclic carbonate group, the synthesis of optically active diol epoxide metabolites of triphenylene was successful. Synthetic endeavors towards the aryne precursor required for the synthesis of diol epoxide metabolites of 7,12-DMBA were moderately successful. To this end, ortho bromination of 2-hydroxy-9,10-dimethylanthracene followed by in situ tosylation with p-tosyl bromide provided the desired aryne precursor. Finally, computational calculations were carried out to corroborate the observed regioselectivity in the Lewis acid-mediated ether bridge opening of 1,4-endoxides.