Synthesis of PAH-metabolites to be used in Environmental Research

Abstract

As environmental pollutants, polycyclic aromatic hydrocarbons (PAHs) are well known to form metabolites which can react with DNA and proteins to cause mutagenesis and create cancer. For chrysene the metabolite (1R,2R)-1,2-dihydrochrysene-1,2-diol has been found to be the most carcinogenic. In order to better understand the metabolism of PAHs and the absolute stereochemistry for PAH metabolites formed in vivo, the pure enantiomer of (1R,2R)-1,2-dihydrochrysene-1,2-diol is needed for further research. The synthetic strategy for the total synthesis of (1R,2R)-1,2- dihydrochrysene-1,2-diol involves the formation of a general chiral bulding block, which can be incorporated as a building-block to form the target molecule, and other PAH metabolites. The key step in the synthesis of the building block is the Shi-epoxidation introducing the chiral centers in the formation of a trans-diol. The trans-diol is further elaborated in order to generate (1R,2R)-1,2-dihydrochrysene-1,2-diol. Polycyclic aromatic hydrocarbons can be formed from a directed ortho metalation (DoM) reaction, followed by a Suzuki-Miyaura cross-coupling reaction and a directed remote metalation reaction (DreM). This methodology was used in the synthesis of chrysen-5-ol and the attempted synthesis of chrysen-6-ol. The unexpected results in the attempted synthesis of chrysen-6-ol led to a study of the birayl rotational barrier study which included several ortho-tolyl amides. However, the rotational barrier could not explain the failed directed remote metalation (DreM) reaction for the synthesis of chrysen-6-ol. From PAHs with a directing group attached a directed ortho metalation (DoM) can be carried out in order to form larger PAHs. The directed ortho metalation was studied for four chrysenyl diethylcarbamates. These reactions resulted in good to excellent yield of the ortho-metalated products.