UCLA

This dissertation describes the development of synthetic methodologies and approaches that leverage strain-driven reactivity to access complex molecules, as well as enzymatic studies and advances in the field of chemical education. The high potential energy stored within strained bonds offers a powerful tool in organic synthesis for the construction of new covalent bonds. Controlling the reactivity of strained molecules, while challenging in many cases, offers a means to form multiple bonds in a single step, under mild reaction conditions, and generate products that may be inaccessible by other means. Herein, several synthetic endeavors are described that seek to leverage strain release to push our understanding of chemical reactivity and gain new entryways into important classes of organic and organometallic compounds. Moreover, two studies in the area of biosynthesis and are described, which take advantage of synergy between chemical synthesis and enzymatic chemistry to access bioactive compounds with high selectivity. Finally, studies in the area of chemical education are described. These efforts seek to make organic chemistry accessible to wider audiences through the development of interactive, globally available educational tools and the creation of a new undergraduate lecture course that highlights the role of organic chemistry in the world around us.

Chapter one describes a perspective on the field of complex molecule synthesis (i.e., total synthesis), with a focus on the power of collaborations across research groups. Although historically competitive, there is a growing spirit of teamwork and collaboration in the field of total synthesis. This chapter discusses recent breakthroughs in both academic and industrial laboratories that have succeeded as a direct result of alliances between research groups.

Chapter two describes progress toward the total synthesis of dodecahedrane, a complex and highly symmetrical hydrocarbon that bears twelve fused rings arranged in a cage-like architecture. Central to our approach is an ambitious [2+2+2+2+2] poly-ene cyclization cascade which would serve to provide new insights into chemical reactivity. Current efforts center around constructing key linkages found in the target by harnessing the strain release of norbornene ring systems to form new carbon–carbon bonds.

Chapter three describes a concise and scalable synthetic approach to precursors to strained intermediates. Although historically avoided due to their high reactivity, strained cyclic alkynes and allenes have demonstrated value in the synthesis of medicinally privileged, polycyclic compounds. These efforts, which provide efficient access to silyl triflate precursors to cyclohexyne and 1,2-cyclohexadiene, serve to enable further studies involving strained alkynes and allenes.

Chapters four and five describe the development of new methodologies that exploit strained aryne intermediates in the synthesis of complex organic and organometallic materials. Both chapters investigate the controlled generation and reactivity of aryne intermediates, as well as engagement of these intermediates in Pd-catalysis to build new ring systems. Chapter four specifically details the development of aryne chemistry “on-the-complex,” wherein fleeting aryne intermediates are reacted with pre-coordinated metal–ligand complexes to form new carbon–carbon bonds. These studies, performed in the context of privileged, photoactive polypyridyl metal complexes, provide an effective strategy to annulate organometallic complexes and access complex metal–ligand scaffolds, while furthering the synthetic utility of strained intermediates in chemical synthesis. Chapter five details the development of Pd-catalyzed reactions of indole and carbazole-based arynes (i.e., hetarynes) to access π-extended heterocyclic materials. The products obtained were applied as ligands in two-coordinate metal complexes to access new OLED emitters.

Chapters six and seven are concerned with uncovering and investigating highly selective reactions catalyzed by fungal enzymes. In particular, chapter six describes the discovery of two groups of enzymes that catalyze distinct reactions, an Alder-ene reaction (previously unknown in biology) and a stereoselective hetero-Diels–Alder reaction. Chapter seven presents studies pertaining to the aminoacylation and thiolation of polyketides in fungi, with a focus on elucidating mechanistic pathways. Both chapters showcase important synergy between chemical synthesis and enzymatic chemistry, and elucidate new enzymatic pathways that ultimately give rise to molecular complexity.

Chapters eight and nine illustrate advances in chemical education. Chapter eight specifically details the development and execution of a new undergraduate course taught by graduate students. The course, entitled Catalysis in Modern Drug Discovery, served to highlight the central role of organic chemistry in drug discovery, while also conveying key concepts in catalysis. Moreover, the course spotlighted the various careers that organic chemists play in the development of new medicines. Chapter nine presents a perspective that highlights our recent efforts to develop interactive resources in chemical education for worldwide usage. In particular, these efforts seek to promote a spirit of innovation in chemical education and spur the development of widely accessible resources that improve learning outcomes and promote positive perception of chemistry in the broader community.