Dissertation

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DIASTEREOSELECTIVE OXIDOPYRYLIUM-OLEFIN [5+2]- CYCLOADDITION, DESIGN AND SYNTHESIS OF A NOVEL CLASS OF SARS-COV-2 3CL PROTEASE INHIBITORS, AND SYNTHETIC APPROACH TO (-)-RASFONIN, AN ANTITUMOR AGENT

thesis
posted on 02.08.2022, 18:04 authored by Monika YadavMonika Yadav

  

Seven-membered ring structures are one of the most important structural motifs found widely in natural products and bioactive molecules. Although several [5+2]-cycloaddition reactions have been developed to construct these seven membered cores, asymmetric cycloaddition reactions are less explored. Described in Chapter-1 is a base mediated intramolecular diastereoselective [5+2]-cycloaddition reaction that afforded highly functionalized seven membered rings in good yields and excellent diastereoselectivities. The high diastereoselectivity is controlled by the alkyl stereocenter and the chain length of the alkene tether. The existing chirality of the substrate can direct the stereochemical outcome of the [5+2]-cycloaddition reaction. Furthermore, this methodology has been applied to synthesize various potent HIV-1 protease inhibitors. 

COVID-19 pandemic has profoundly affected life around the globe and costed us 6 million lives. Therefore, there is an urgent need for rational design of new drug candidates to specifically target different SARS-CoV-2 proteins. Recently, Pfizer developed an FDA-approved antiviral therapeutic agent, Paxlovid, targeting SARS-CoV-2 3CLpro. Chapter-2 discusses a concise synthetic route to synthesize active component of Paxlovid, Nirmatrelvir, in 6-steps without any epimerization. We have also developed a series of potent covalent inhibitors targeting SARS-CoV-2 3CLprotease and compared the antiviral activities of these inhibitors with that of Nirmatrelvir. 

In the final chapter, a concise partial synthesis of the segment A of (-)-Rafonin is discussed. (-)-Rasfonin is an antitumor agent that induces apoptosis in ras-dependent cells. We have proposed an asymmetric chiron approach to install the α-pyranone ring of rasfonin. Our goal is to perform SAR studies on this natural product by designing various analogues. 

History

Degree Type

Doctor of Philosophy

Department

Chemistry

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Arun K. Ghosh

Additional Committee Member 2

Suzanne C. Doucette Bart

Additional Committee Member 3

Christopher Uyeda

Additional Committee Member 4

Elizabeth I. Parkinson

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