Enantioselective Total Syntheses of Both Enantiomers of Amphirionin-4 and Design and Synthesis of New Generation HIV-1 Protease Inhibitors
Abstract
Amphirionin-4 is a natural product containing a syn-tetrahydrofuran ring and a linear polyketide side chain. Amphirionin-4 showed highly potent cell proliferation-promoting activity (950%) on murine bone marrow stromal ST-2 cells at 0.1 ng/mL concentration. We have accomplished the enantioselective total syntheses of both enantiomers of amphirionin-4 and we established the absolute configuration of C-4 and C-8 centers by using modified Mosher ester analysis. Our synthesis highlights an enzymatic lipase catalyzed resolution of racemic cis-hydroxy lactone to access the both enantiomers in high optically active form. The syn-functionalized tetrahydrofuranol core moieties were obtained through Lewis acid catalyzed oxocarbenium ion mediated high diastereoselective syn-allylation. The polyene side chain was efficiently constructed by utilizing iterative Stille-coupling reactions. Nozaki-Hiyama-Kishi coupling reaction was used to introduce the remote C-8 allylic alcohol stereocenter through 1,4-stereoinduction. The Pauson-Khand reaction was used for the synthesis of a series of syn-fused bridged tricyclic P2 ligands. Bridged tricyclic ligands containing PIs were designed to increase the hydrophobic interactions along with strong network of hydrogen bonding interactions with the active site of HIV protease. We have synthesized several novel HIV-1 PIs incorporating newly designed P2 ligands in combination with 4-methoxybenzenesulfonamide, aminobenzothiazole and aminobezooxazole as P2'-ligand. Also, we investigated the effect of fluorine atom on the phenylmethyl side chain on P1-ligand. Many of these inhibitors showed highly potent enzyme inhibitory and antiviral activity against multidrug resistant HIV-1 variants. To further optimize the bis and Tp-THF ligands to enhance the hydrogen bonding interactions as well as van der Waals interactions within the protease active site, we designed and synthesized a new class of next-generation HIV-1 protease inhibitors. The Diels-Alder reaction was utilized to access the newly designed unprecedented crown-like tetrahydropyrano-furan (Crn-THF) as P2- ligands. A series of PIs were synthesized by incorporating Crn-THF as P2-ligand in combination with various (R)-hydroxyethylsulfonamide isosteres. Most of these inhibitors displayed excellent enzyme inhibitory and antiviral activity over other approved PIs. Our protein-ligand X-ray crystal structure of these inhibitors showed extensive interactions in the active site responsible for their exceptional activity.
Degree
Ph.D.
Advisors
Ghosh, Purdue University.
Subject Area
Organic chemistry
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