Modular Synthesis and Hydroalkylation of Vicinally Functionalized Ketopiperazines: A solution to the Piperazine Problem
Date of Degree Completion
Master of Science (MS)
Timothy K. Beng
Second Committee Member
Third Committee Member
Fourth Committee Member
The stereocontrolled synthesis of functionalized piperazines is of great interest to pharmaceutical companies owing to their multiple biological activities such as antidepressant, antiparasitic, anticancer and antiretroviral. Current methods towards functionalized piperazines include intramolecular cyclization of appropriately tethered on acyclic precursors as well as α-C–H functionalization of intact piperazine rings. Although effective for the most part, these methods suffer from drawbacks such as the use of expensive catalysts, potentially toxic reagents, limited scope and functional group compatibility. Seeking to side-step some of the aforementioned limitations, we herein describe a step-economical-, cost-effective-, transition metal-free-, and mild approach to highly functionalized piperazines, including [3.3.1]-bicyclic piperazines. The success of a novel enolate hydroalkylation methodology hinges on a cascade reaction triggered by the addition of allyl magnesium bromide to a vicinally functionalized piperazinonate. Furthermore, we have successfully synthesized fluorinated ketopiperazine, in hopes of potentially modulating biological properties such as pharmacokinetic and physicochemical properties. The [3.3.1] azabicyclic piperazinols and fluorine-containing 2-oxopiperazines are subsequently engaged in structure-activity-relationship (SAR) studies on neglected tropical diseases (NTDs), including leishmaniasis.
Moreno, Antonio, "Modular Synthesis and Hydroalkylation of Vicinally Functionalized Ketopiperazines: A solution to the Piperazine Problem" (2019). All Master's Theses. 1215.