Electrocatalysis for the synthesis of chiral and PET imaging pharmaceuticals

Project Summary/Abstract Chiral drugs and radiolabelled compounds are two general classes of highly sought molecules for the detection, treatment, and prevention of disease. Chiral compounds are present in the majority of complex bioactive drugs. On the other hand, radiolabeled compounds are widely used as imaging agents for positron emission tomography (PET).

Despite the many recent advancements in synthetic organic chemistry, such as in transition-metal (TM) catalysis, the incorporation of functional groups to construct stereogenic centers and/or install radioactive nuclei in a safe and sustainable method remains challenging. Thus, providing opportunities to develop novel approaches in organic synthesis relevant to drug discovery.

Electrosyntheses have shown application in organic synthesis; however, it suffers from achieving product selectivity and lacks the ability to construct stereogenic centers.

The overall goal of this project is to integrate electrochemistry and transition-metal catalysis to provide solutions on the challenges in organic synthesis particularly in the assembly of chiral and radiolabeled drugs.

This grant builds on existing collaboration between the Minteer Lab (electrocatalysis, electroanalysis) and the Sigman Lab (asymmetric catalysis, data science) in the development of electroactive compounds for battery and synthesis applications.

Integration of my expertise (organic chemistry, transition metal catalysis, and organometallic chemistry) with Minteer and Sigman will bring a collective capability to accomplish the overall goal.

The central hypothesis of this application is that through the use of electrochemical energy, non-toxic TM can be used as electrocatalysts to selectively install functional groups/atoms that are often used as radioactive elements in PET tracers while generating a stereogenic center.

Specifically, we will (Aim 1) develop cobalt electrocatalytic asymmetric reactions to convert organohalides into chiral carboxylic acids, nitriles, and fluorinated compounds. This electrocatalytic approach will also allow us to discover new reactions that are valuable in medical applications.

Through catalyst design and electroanalysis, we will develop (Aim 2) TM-electrocatalysts capable of activating and functionalizing inert amide bonds (most represented polar bond in organic and biomolecules). This will provide a late-stage functionalization in amide-containing marine products and polypeptides.

Radiopharmaceuticals for PET imaging require rapid preparation and delivery to patients due to their short-lived radioactivity (t1/2 = 20.4 and 110 min for 11C and 18F radionuclide, respectively).

For the first time, we will use the strategic merger of electrochemistry and TM-catalysis to provide a new synthetic approach to deliver chiral radiopharmaceuticals (Aim 3).

The transformations in Aims 1 and 2 were carefully chosen based on their high potential to be adapted for the assembly of radiopharmaceuticals.

Overall, this project will deliver unique, organic transformations that will directly impact the complex process of drug discovery.