Abstract

An efficient parallel synthesis was designed to provide libraries of estradiol mimics that can potentially interact with different biological targets associated with estradiol-related diseases. Two libraries of 75 members each were synthesized around a non-steroidal core by adding three levels of molecular diversity. Hydroxybenzaldehydes (1^st level of diversity), protected as a methoxymethyl ether, first reacted with primary amines (2^nd level of diversity) under reductive amination conditions. The resulting secondary amines next reacted with 4-bromo-1,2-epoxybutane to provide epoxide derivatives as precursors of the 3^rd level of diversity. Various nucleophiles were then used to open each epoxide. Methyl isocyanate scavenger was finally used to trap out the excess amine and the protecting group was removed by hydrolysis to provide the final compounds.

Keywords: Epoxide opening, estradiol mimic, liquid-phase chemistry, non-steroidal derivative, parallel synthesis, phenol library, reductive amination.