Design and synthesis of novel cycloamide- and oxindole-derived HIV protease inhibitors

This thesis describes the design and synthesis of novel HIV protease inhibitors incorporating cycloamide-derived P2-P1 macrocycles as well as inhibitors containing P2' oxindole rings.;Part one of the thesis details the enantioselective synthesis of a Tyr-based hydroxyethylamine isostere utilizing Sharpless asymmetric epoxidation with D-DET as the key step. A convergent and flexible synthesis employing a diene-ketene electrocyclization is utilized to prepare various 3-hydroxy-2-alkyl-benzoic acid derivatives. The olefin-containing aromatic P2 ligands and the olefinic ether-derived Tyr P1 moiety are efficiently closed in a ring-closing metathesis reaction employing Grubbs' catalyst and provide 16--19-membered macrocycles. The macrocycles exhibit excellent (0.2 nM to 20 nM) in vitro potency against HIV protease with the smaller ring sizes being most effective.;Part two of this thesis describes the design and synthesis of novel HIV protease inhibitors containing an oxindole ring in the P2 ' position. The oxindole ligands are efficiently synthesized starting with commercially available isatin via a Grignard addition to the ketone followed by chlorination using thionyl chloride. The chlorides thus produced undergo substitution by a variety of amines to provide the quaternary carbon-bearing oxindoles in good yields. Inhibitors with various groups on the tertiary amine as well as the oxindole ring are tested and displayed excellent potency towards HIV protease. Additionally, novel conformationally constrained spirocyclic inhibitors were synthesized using Grubbs' catalyst promoted ring closing metathesis which contain 6- to 8-membered rings between the tertiary amine and the quaternary oxindole center.