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

<p>(+)-Monocerin is a dihydroisocoumarin natural product that is consisted of a 2,3,5-trisubstituted tetrahydrofuran moiety with all-<i>cis</i> stereochemistry. (+)-Monocerin showed very potent antimalarial activity (IC₅₀ = 680 nM) against <i>Plasmodium falcifarum, </i>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 <i>syn</i>-allylation reaction and an Oxa-Pictet-Spengler cyclization to construct an isochroman structure of (+)-monocerin in <i>one-pot</i>. 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.</p> <p>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 (<i>tc-</i>THF) moieties as P2-ligands. A series of protease inhibitors were synthesized by incorporating <i>tc</i>-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.<br></p><p><i></i></p> <p> </p>