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Enantioselective Total Synthesis of (+)-Monocerin and Design and Synthesis of Potent HIV-1 Protease Inhibitors

thesis
posted on 02.12.2020, 15:47 by Daniel S Lee

(+)-Monocerin is a dihydroisocoumarin natural product that is consisted of a 2,3,5-trisubstituted tetrahydrofuran moiety with all-cis stereochemistry. (+)-Monocerin showed very potent antimalarial activity (IC50 = 680 nM) against Plasmodium falcifarum, which is a multi-antimalarial drug resistant K1 strain. Our synthesis involves a Sharpless dihydroxylation as one of the key steps to efficiently provide the optically active lactone intermediate with high enantiomeric purity. Our synthesis also features a tandem Lewis acid-catalyzed diastereoselective syn-allylation reaction and an Oxa-Pictet-Spengler cyclization to construct an isochroman structure of (+)-monocerin in one-pot. By employing several different Lewis acids and protecting groups, this allylation reaction has been thoroughly studied. The enantioselective total synthesis of (+)-monocerin and its acetate derivative was accomplished in 10 and 11 steps with 9% and 8.6% overall yield, respectively.

To further optimize the hydrogen bonding interactions as well as Van der Waals interactions within the active sites of HIV-1 protease inhibitors, we have designed and synthesized a new class of HIV-1 protease inhibitors incorporating trisubstituted-chiral-tetrahydrofuran (tc-THF) moieties as P2-ligands. A series of protease inhibitors were synthesized by incorporating tc-THF as P2-ligand in combination with the known 4-methoxybenzenesulfonamide and 4-aminobenzenesulfonamide isosteres as P2’-ligands. The effect of stereochemistry of the chiral substituents on the binding affinity was thoroughly examined. Most of these newly synthesized inhibitors displayed potent enzyme inhibitory activity.

History

Degree Type

Doctor of Philosophy

Department

Chemistry

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Arun K. Ghosh

Additional Committee Member 2

Mingji Dai

Additional Committee Member 3

Chittaranjan Das

Additional Committee Member 4

Mark Lipton

Licence

Exports

Licence

Exports