Coumarins, macrocycles, and indazoles: Solution and solid phase synthesis of libraries of biologically interesting heterocycles

Cystic fibrosis (CF) is one of the most common fatal genetic diseases among Caucasians which has prompted us to search for small molecule activators of the cystic fibrosis transmembrain regulator (CFTR) protein. One known class of heterocycles that are known activators of CFTR are benzo[c]quinolizinium derivatives. In an effort to make benzo[c]quinolizinium derivatives, we have discovered an alternative route to 4-hydroxycoumarins. A solid phase strategy has been developed for the creation of a small library of 3-aryl-4-hydroxycoumarins. The cleavage strategy employs a cycloelimination cyclization in the key coumarin forming transformation. A two unit diversity library of 3-aryl-4-hydroxycoumarins has been employed to explore this cycloelimination from the solid support. This work is described in Chapter 1.;Polyheterocyclic macrocycles have great potential as biologically active drug targets and are also interesting synthetic targets. The synthesis of libraries of structurally diverse macrocycles could accelerate the search for important new scaffolds for drug discovery. Macrocycles have many favorable qualities that are illustrated by large biomolecules, such as tight receptor binding, which leads to high selectivity and potency. The focus of this research is to explore the utility of using the 1,3-dipolarcycloaddition reaction as a macrocyclization tool. Macrocyclization by both isoxazole and isoxazoline formation was accomplished using the 1,3-dipolarcycloaddition reaction. This work is described in Chapter 2.;A new heterocyclization method of nitrogen-containing heterocycles employs an N,N bond-forming heterocyclization to afford a 2H-indazole ring. This method offers the advantage of requiring no expensive or toxic metals to mediate heterocycle formation and proceeds under mild base at relatively low temperature in an alcoholic solvent. The one-step heterocyclization of o-nitrobenzyl amines to 3-alkoxy-2H-indazoles is reported. The electronic nature of the nitrophenyl group, the steric and electronic nature of the benzylic amine group (R1), and the nature of the alcoholic solvent affect the efficiency of this heterocyclization reaction (∼40--90%). A small library of 3-oxysubstituted 2H-indazoles was synthesized from 2-nitrobenzyl amines to give 2H-indazoles. This work is described in Chapter 3.