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

Abstract

(+)-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.