Synthesis of and reactivity studies with 19-peroxide-androstenedione derivatives: analogues of a proposed aromatase intermediate

Abstract

Human placental aromatase is a cytochrome P 450 enzyme system which converts steroidal androgens to steroidal estrogens. Three sequential oxidative steps are involved in the conversion, the first two leading to 19-hydroxy (2) and 19-oxo intermediates (3), respectively. The mechanism of the third step has remained elusive although one proposal which has remained consistent with experimental data involves formation and aromatization of a 19,19-hydroxyferric peroxide (5) intermediate. This study discusses the synthesis of 19,19-methoxy hydroperoxide (12)via ozonolysis, evidence for its formation, and studies of its reactivity under different conditions. Another approach was used to synthesize 19,19-hydroxy peroxide derivatives via the 19-aldehyde (3b). The reactivity of these derivatives was also explored. An analogous reaction involving 18O-HOOH was carried out to investigate the mechanistic details of an unprecedented intramolecular epoxidation reaction. None of the peroxide derivatives were converted into estrogen or estrogen derivatives under the conditions examined, and the possible implications for the aromatase reaction are discussed.