Part I. Diels-Alder reactions of enyne dienophiles. Part II. Total synthesis of spirotenuipesines A and B. Part III. Cortistatins as inspirations for methodology development and analog synthesis

The first part of the thesis describes highly chemo- and regio-selective Diels-Alder reactions of enyne dienophiles to the synthesis of polysubstituted aromatic compounds. In all the cases at hand, the cycloaddition occurs exclusively at the triple bond of enyne dienophiles with the vinyl moiety dictating the regio-chemical outcome. The regioselectivity of the Diels-Alder reaction of beta,beta'-connected dienyl dienophile is also controlled by the vinylester moiety. Theoretical studies have been carried out. The calculations gave excellent agreement with the experimental results.;The second part of the thesis describes the total synthesis of neurotrophically active small molecule natural products spirotenuipesines A and B. The highly diastereoselective synthesis features (1) an improved RCM route to the tetrasubstituted cyclopentenyl system, 36, (2) a tethered cyclopropanation and radical triggered fragmentation strategy to the synthesis of the key bicyclic lactone 51b, (3) a Diels-Alder reaction between alpha-methylenelactone dienophile 56 and synergistic diene 71 to assembly the spirocyclic system. We have further developed a strategy by which to access optically active spirotenuipesines A and B through the synthesis of enantioenriched 35.;The third part of the thesis describes our synthetic studies toward the anti-angiogenic cortistatin steroidal alkaloids. Inspired by the structural motif of the cortistatins, three synthetic strategies to the synthesis of the cortistatin core have been developed. The first approach involves an oxidative dearomatization cyclization strategy to generate the oxabicyclo[3.2.1]octene ring system. In the second approach, a novel alpha,beta-unsaturated nitrone-aryne [3+2] cycloaddition has been developed. The resulting benzoisoxazolines underwent reduction-elimination-electrocyclization sequence to furnish a variety of polysubstituted 2H or 2-alkylated-1-benzo-pyrans. The application of this methodology was further demonstrated in the synthesis of the oxabicyclo[3.2.1]octene moiety of cortistatin A. The third and current approach features a modified Snieckus-type domino reaction and the Masamune alkylative dearomatization cyclization to construct the core matrix of the cortistatins. The modified Snieckus-type domino reaction and the Masamune alkylative dearomatization cyclization have proven to be quite general, providing an entry to access stereo-diverted analogues of the cortistatins.