Metal-Templated Assembly of Heterocyclic Rings via Nucleophilic Cyclization of Cyclopropenes

This thesis is focused on the development and application of methods for the intramolecular nucleophilic addition of tethered nucleophiles to cyclopropenes. Addition of carbon-, nitrogen, and oxygen-nucleophiles was demonstrated to provide access to γ-aminobutyric acid (GABA) derivatives and biologically relevant cyclopropane-fused heterocyclic rings (heteroazepanones, heteroazocanones, and pyrrolidinones). The thesis is divided into five chapters, which discuss not only the development and elaboration of our chemistry, but also biological importance and alternative methods for synthesis of target heterocycles presented in literature. Chapter one is a review of biological activity, occurrence in nature, and synthetic approaches for the preparation of heteroazepanones and heteroazocanones. The chapter will describe methods based on cyclization and ring expansion reactions, as well as multicomponent and tandem methods. Chapter two focuses on the one-pot synthesis of various γ-aminobutyric acid (GABA) amides through unassisted nucleophilic addition of primary and secondary amines across the double bond of cyclopropene-3-carboxamides. Initial nucleophilic attack is followed by a ring opening of the resulting donor-acceptor cyclopropanes. Subsequent in situ reduction of enamine or imine intermediates allows to access substituted GABA derivatives. Chapter three describes a formal intramolecular nucleophilic substitution reaction of bromocyclopropanes with nitrogen ylides generated in situ from N-benzyl carboxamides. This reaction represents the 5-exo-trig cyclization through intermolecular base-assisted nucleophilic addition of tethered benzylic anion to cyclopropenes generated in situ by dehydrohalogenation of bromocyclopropanes. Chapter four describes modular assembly of enantiopure cyclopropane-fused oxazepanones through a strain-release-driven, cation-templated intramolecular nucleophilic addition of tethered alkoxides to prochiral cyclopropenes. The mechanism of enantiomeric induction is detailed. The biological profile exhibited by some of obtained 2-oxa-5-azabicyclo[5.1.0]octan-6-ones is characterized by promising activity against Mycobacterium abscessus coupled with apparent low general toxicity against cultured human cells. The final chapter covers ring-retentive 7- and 8-exo-trig nucleophilic attack of tethered nitrogen-based nucleophiles at cyclopropene double bond. The described potassium-templated cyclization proceeds in highly regio- and diastereoselective fashion and provides expedited access to previously unknown drug-like scaffolds including several structures with promising anti-cancer properties