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 (1st level of
diversity), protected as a methoxymethyl ether, first reacted with primary amines (2nd 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 3rd 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.
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