The goal of this research is to design a method for an atroposelective cyclodehydration to obtain atropisomerically stable 3-aryl pyrrolopyrimidines. We found that the S<sub>N</sub>Ar of hydrazine into a pyrimidine scaffold followed by a cyclodehydration with ketone yielded atropisomerically stable PPs. Privileged chiral catalysts such as quinine-based cinchona alkaloid derivatives that have basic tertiary quinuclidine nitrogen atom have demonstrated enantioselectivity over a wide range of reactions. Obtained preliminary data shows that chiral quaternary ammonium salts could render the reaction enantioselectivity, giving greater than 75:25 e.r. in good yields. Similar cyclization approach will be applicable to many relevant atropisomeric scaffolds. Moreover, we are also working on the development of RET degrading Proteolysis targeting chimera (PROTAC) to evaluate RET degradation as a potential therapeutic strategy for Neuroblastoma and other RET-driven cancers.  Characterization of our best RET inhibitor in cellular models of Neuroblastoma showed promising results which inspired the idea of incorporating scaffold into PROTACs, as we hypothesize that degradation of these mutants will overcome the pharmacological liabilities caused by a lack of selective inhibition.

Development of atroposelective methodology for pyrazolopyrimidine-based scaffolds and RET kinase degraders for biomedical applications

ACS Spring 2022

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