Testing the boundaries of novel Friedel-Crafts-type methodologies inspired by n-heteroaromatic medicinal targets

Abstract

Methodology development is an essential pursuit to enable the synthesis of pharmaceutically-relevant targets. The emergent concept of privileged scaffolds has provided a framework for focused synthetic methodology development toward polycyclic heteroaromatic compounds with inherent and important bioactivities. This thesis explores novel applications of the Friedel-Crafts reaction toward three medicinal compounds and their privileged scaffolds: flubromazepam, a 1,4-benzodiazepine; tronocarpine, a tetrahydro-7,11-methanoazocino[1,2-a]indole; and rhazinicine, a tetrahydroindolizine. Several 1,4-benzodiazepine positional isomers were synthesized and characterized for the first time. Additionally, significant advances in knowledge were accomplished toward the reactivity and stereochemical behavior of donor-acceptor bicyclo[3.1.0]hexanes, an understudied class of DACPs, in intramolecular ring-opening cyclizations, and a novel formal [3+2] cycloaddition of a C5-substituted D-A oxabicyclo[3.1.0]hexane was demonstrated.