Synthesis of Haloperidol Ethanedithioketal HIV-1 Protease Inhibitors: Magnesium Chloride Facilitated Addition of Grignard Reagents

Haloperidol ketals and ethanedithioketals of interest as HIV-1 protease inhibitors were synthesized by addition of organolithium and organomagnesium reagents to ketone precursors already containing the ketal or thioketal functionality. Addition of Grignard reagents to the thioketal containing ketone was enhanced remarkably, and to the ketal containing ketone moderately, by the addition of magnesium chloride. The effect of magnesium chloride is attributed to its ability to competitively prevent chelation of the Grignard reagent and proton abstraction from the 4-oxopiperidine ring. The biological activities of the ketals and thioketals indicate that the thioketal function conveys greater ability to inhibit the HIV-1 protease than the ketal function.