The Development of New Methodologies for the Synthesis of Biologically Active Compounds

This thesis details the author's research on four research projects, each of which is concerned with the chemical synthesis (CS) of either natural or designed targets that embody carbo or hetero cyclic frameworks of relevance in medicinal chemistry. Chapter One provides an introduction as to how CS is used as a tool for aiding biological and medical (pharmaceutical) research. A summary of the four research projects follows and each of these is then detailed in the subsequent chapters. Chapter Two is concerned with the synthesis of certain ring fused gem dihalocyclopropane and their electrocyclic ring opening for the purposes of constructing new heterocyclic frameworks. Chapter Three describes the establishment of new methodologies allowing for the synthesis of functionalized benzofurans, indoles and phthalanes. In particular, it describes tandem Ullmann Goldberg cross coupling cyclopalladation reductive elimination reactions that have been deployed for this purpose. Chapter Four details the author's efforts to establish a total synthesis of the structurally novel diaryl cycloheptanoid giffonin U, a macrocyclic and biologically active compound recently obtained from the leafy covers of hazelnuts. The work described in Chapter Five concerns efforts to establish the cellular targets of the cancer therapeutic agents CX 5461 and PMR 116 by adorning them with suitably located alkynyl residues that could be engaged in click reaction with azides bearing biologically relevant tags. Chapter Six details all of the experimental protocols and spectral data that underpin the research work described in Chapters Two to Five

Tandem Ullmann-Goldberg Cross-Coupling/Cyclopalladation-Reductive Elimination Reactions and Related Sequences Leading to Polyfunctionalized Benzofurans, Indoles, and Phthalanes

On exposure to a combination of Cu[I]- and Pd[0]-based catalysts, compounds such as 1 and 7 engage in tandem Ullmann-Goldberg cross-coupling and cyclopalladation-reductive elimination reactions to give benzofurans such as 8. Related reactions involving hetero-Michael additions of o-halogenated phenols or anilines to propiolates and the Pd[0]-catalyzed cyclization of the resulting conjugates provide, in a one-pot process, alternately functionalized benzofurans, indoles, or phthalanes.We thank the Australian Research Council and the Institute of Advanced Studies for financial support including the provision of scholarships to F.K. and M.A. as well as a postdoctoral fellowship to Y.V. F.M. thanks the Higher Education Council of the Government of Pakistan for support, and M.S. acknowledges the support of the Islamic Government of Ira