New Developments in Heterocycle Synthesis: Applications of an Anti-Aminopalladation Mechanism

Abstract

Biologically active compounds, such as molecules isolated from natural sources like plants and marine sponges, have long been of interest to the synthetic chemistry community. Synthetic routes towards these biologically interesting compounds are constantly being sought after and improved upon by synthetic chemists, because efficient synthetic routes yield not only the compound in question in mass quantitites, but also allow for the formation of a library of compounds bearing small changes in structure that are not found in the originally isolated compound. These small changes can potentially have dramatic effects on the biological activity of the compounds in question. Nitrogen containing heterocycles appear in a wide variety of these aforementioned biologically active compounds, and for this reason have long been an attractive target to the synthetic community. Heterocyclic scaffolds such as substituted pyrrolidines are present in compounds that display a wide variety of biological activity, such as antifungal, antibiotic, and antitumor properties. Cyclic guanidines are also present in a large number of biologically interesting molecules, such as compounds that display antibiotic, immunosuppressive, and neurotoxic properties. While synthetic methodologies to access the scaffolds in question currently exist, the majority of them rely on preexisting substitution present in the substrate to afford the desired substituted products. This precludes the ability to rapidly synthesize a library of compounds with various substitution patterns that can then be assayed for changes in biological activity. The research described in this dissertation details the development of a methodology to synthesize substituted, nitrogen containing heterocycles in a palladium catalyzed, modular coupling reaction. Chapter 1 outlines the biological relevance of nitrogen containing heterocycles, and it details the previous efforts of the Wolfe group to synthesize the molecular scaffolds in question. Chapter 2 describes the synthesis of substituted pyrrolidines via a newly developed, anti-aminopalladation methodology. Substituted pyrrolidine products bearing previously unusable N-tosyl and N-trifluoroacetyl protecting groups were afforded in good yield. Chapters 3 and 4 detail the synthesis of substituted, cyclic guanidines from acyclic N-allyl guanidine substrates. Chapter 3 focuses on coupling said guanidine substrates with aryl halides/triflates, in which substrates bearing cleavable N-cyano and N-tosyl protecting groups were utilized. Finally, Chapter 4 describes the successful coupling of guanidine substrates bearing N-cyano and N-tosyl protectin groups with OBz-protected amine electrophiles in a variation on a 1,2-diamination reaction.