Synthesis of (+/-)-trans-7,8-dihydrodiol of 6-fluoro-benzo[a] pyrene via hydroxyl-directed regioselective functionalization of substituted pyrene

Synthesis of (+/-)-trans-7,8-dihydroxy-6-fluoro-7,8-dihydrobenzo[a] metabol ite from 6:fluoro-benzo[a]pyrene, is described. Position 6 of 7,8,9,10-tetr ahydrobenzo[a]pyren-7-ol (1) was functionalized by bromination with N-bromo saccharin. Regioselectivity in the bromination is thought to derive from a substrate-reagent hydrogen bond. NMR evidence is offered to support this mo del. The 6-bromo derivative 2 was subjected to dehydration followed by brom ine-lithium exchange. Quenching the lithio intermediate with NFSi afforded the g-fluoro derivative 4. Prevost reaction on the 7,8 double bond resulted in the trans dibenzoate 5 (established by comparison to a cis derivative p repared by osmium tetroxide cis dihydroxylation). Introduction of the 9,10 double bond by a bromination-dehydrobromination procedure, followed by hydr olysis, gave racemic trans-7,8-dihydrodiol 7. Resolution of the enantiomers was achieved by chiral HPLC, and the absolute configurations of the early and late eluting isomers were determined through CD spectroscopy by compari son with the metabolically obtained (7R,8R)-dihydrodiol.