3,4-Epoxyprecocenes as Models of Cytotoxic Epoxides: Synthesis of the Cis Adducts Occuring in the Glutathione Metabolic Pathway

Article abstract of DOI:10.1021/jo00293a012

The adducts of 3,4-epoxyprecocene II (1b) with N-acetyl-L-cysteine, and glutathione (GSH), in which a formal syn addition of the thiol reagent to the oxirane has taken place, with the atom linked to the benzylic position of the benzopyranyl skeleton of 1b, have been synthesized.A stereochemical correlation between the two sets of diastereomeric cis adducts 3, 5, and 6 formed, i.e. the 3R,4S and 3S,4R series, has been established by spectroscopic, chromatographic, and enzymatic means.To assign the absolute configuration of these adducts, a synthesis of chiral 1b(3R,4R), using the cysteinyl moiety itself as reagent for resolution of the precursor racemic bromohydrin 7, has been developed.Regarding the influence of the reaction conditions on the stereochemical course of the oxirane cleavage, the addition of methyl esters of L-cysteine or its N-acetyl derivative to 1b in neutral organic solvents led to the corresponding cis adducts 4 and 2, respectively, with a high degree of stereoselectivity.On the other hand, in aqueous media the stereochemical outcome of the reaction of GSH with epoxide 1b depends on the solvent polarity and pH.Thus, while above pH13 the trans diastereomeric pair of adducts is almost quantitatively formed, a significant proportion of the corresponding cis conjugates is obtained within the pH range 8.5-10.5 (up to 24percent).This result suggests that the cis conjugates could also exert a role in the detoxification mechanisms of highly reactive epoxides.