Studies Towards the Synthesis of Nitrogen Containing Heterocycles Using Au(I) Catalysis and the Photochemical Synthesis of Cyclopropanes

Abstract

The work presented in this thesis will be split into two parts. Part I of this thesis focuses on the utilization of gold(I) catalysis towards heterocyclic and total synthesis. Gold(I) catalysis is strategically applied in developing a new synthesis of tetracyclic indole products in addition to the total synthesis of the complex alkaloid natural product brevianamide A. Part II of this thesis shifts gears from gold(I) catalysis and focuses on the photochemical synthesis of cyclopropane building blocks. This strategy relies on the ring contraction of α-arylated thietane-1,1-dioxide substrates (four-membered cyclic sulfones) that extrude sulfur dioxide (SO2) upon irradiation with ultraviolet light. In Chapter 1, a general and non-comprehensive introduction to homogeneous gold(I) catalysis is discussed. This chapter is meant to help prime the reader in understanding the concepts of reactivity that are referenced in both Chapters 1 and 2. Brief sections on relativistic effects, catalyst structures, general reactivity modes, and applications are provided. In Chapter 2, the exploration of a unique and novel approach towards the rare Au(I) catalyzed α-Csp3-H functionalization of tertiary amine substrates was investigated. Direct C-H bond functionalization for the formation of new C-C or C-X bonds is an incredibly useful and straightforward strategy. Our approach to this challenge relied on combining and leveraging the unique reactivity of highly electrophilic α-imino gold carbene intermediates with redox-neutral hydrogen atom transfer from tertiary amine motifs. To the best of our knowledge, no such reports of these intermediates have been used in tandem with the Csp3-H functionalization of tertiary amines despite having been used in numerous other transformations with many different nucleophiles. At the outset, we were cognizant of the favorable coordination ability of Lewis basic tertiary amines with Lewis acidic cationic Au(I) complexes. This interaction would likely prevent catalysis from taking place, not only from an alkyne activation standpoint but also from the perspective of hydride transfer. A work around to this problem was rationally designed and implemented in the form of a malonate blocking group. The malonate was incorporated into the substrate structure and was key to the success of the reaction through the exertion of steric, electronic, and conformational effects. Importantly, these effects seemed to be operating in synergy rather than in competition with one another. After thorough optimization, we also demonstrated that this reaction is broadly applicable, tolerates different functional groups, and affords us valuable tetrahydro--carboline products that can be selectively oxidized and functionalized to result in biologically and synthetically relevant structural motifs. In Chapter 3, the total synthesis of racemic brevianamide A using gold(I) catalysis as a key step was investigated. Brevianamide A is a prototypical dioxopiperazine natural product that was isolated in 1969 by Birch and Wright from the fungus Penicillium brevicompactum. In addition to its bicyclo[2.2.2]diazaoctane substructure, brevianamide A possesses a characteristic pseudoindoxyl motif and two adjacent quaternary centers. These features make this natural product a challenging synthetic target, especially when it comes to generating structural complexity efficiently. Previous syntheses of brevianamide A installed the key structural features of the natural product (mentioned above) in a less than ideal manner. Based on these considerations, a new synthetic approach towards brevianamide A that would shortcut and improve access to the natural product was designed and executed. Key to our synthesis is the strategic use of a gold(I) catalyzed cascade process that quickly assembles the characteristic pseudoindoxyl motif, reverse prenyl group, and two quaternary centers in a single step. This is achieved using the readily available prenyl alcohol in conjunction with gold(I) catalysis to introduce the reverse prenyl unit at C2 of the natural product. Thanks to the increase in structural complexity that can be achieved with gold catalysis, we were able to develop two complementary and concise routes to racemic brevianamide A from readily available amino acid building blocks. Moreover, the conditions necessary to affect the formation of the natural products bicyclo[2.2.2]diazaoctane core proved to be highly compatible with gold catalysis, allowing for the development of a one-pot process and further streamlining our new approach towards this natural product. As a result, we have published the shortest and highest yielding synthesis of brevianamide A to date. In Chapter 4, the photochemical ring contraction and synthesis of α-arylated thietane-1,1-dioxide substrates were investigated towards accessing cyclopropane building blocks. The cyclopropane motif is very sought after in medicinal chemistry as a privileged structural motif and is also present in various natural products, agrochemicals, and fragrances. Common methods to access cyclopropanes have traditionally relied on either cycloaddition or nucleophilic displacement strategies and while successful, these approaches can be limited in terms of their scope and ability to access substrates in a modular manner. Furthermore, scalability and reaction efficiency are a common issue owing to the use of highly reactive intermediates and/or reagents. With these issues in mind, we have developed an uncommon photochemical ring contraction strategy that uses thietane-1,1-dioxide precursors containing an aryl ring chromophore. Light is a cheap and renewable energy source, offering the potential to circumvent issues of reactivity and selectivity of the more traditional cyclopropanation methods. Optimization of photochemical conditions allowing access to the cyclopropane scaffolds was therefore developed and studied. While initially promising, substrate synthesis utilizing reported enamine and/or ketene acetal [2+2] cycloadditions with sulfonyl chlorides proved to be unsatisfactory for the introduction of modularity and diversity. To alleviate this issue, an investigation into the use of the unsaturated thiete-1,1-dioxide derivatives was performed and enabled access to several thietane-1,1-dioxide derivatives. Subsequently, a scope of the ring contraction process was extended to include the synthesis of a diverse set of cyclopropane building blocks, particularly cyclopropylamine structures that are valuable in medicinal chemistry. Additionally, a brief overview of the future directions for the project is also discussed.