Studies Towards the Total Synthesis of Atropurpuran and the Arcutines

Compounds isolated from natural sources serve as an inspiration for current drug design and development due to their broad biological activities. However, these desirable compounds are often isolated in minute quantities that often limit extensive biological evaluation and further medicinal applications. The diterpene atropurpuran and its diterpene alkaloid analogs, the arcutines, are isolated from the plant roots of various Aconitum plants that are used in the traditional Chinese medicine “Cao-Wu” for the treatment of diseases associated with pain and inflammation. However, the biological activity of atropurpuran and the arcutines has yet to be elucidated. These compounds pose a synthetic challenge as they bear an intriguing tetracyclic carbon core that has never been observed in any other diterpene or diterpene alkaloid natural products. We describe a unique approach to atropurpuran and the arcutines that takes advantage of their inherent symmetry and relies on a key pseudo-symmetric cyclic 1,3-dione intermediate. This approach exploits the inherent the reactivity of the compounds and will enable an efficient synthesis of atropurpuran and the arcutines when coupled with an aluminum chloride-mediated Dieckmann cyclization strategy that will provide rapid access to the cyclic 1,3-dione. Chapter 1 provides a brief overview of the historical use of diterpene alkaloids and their recent development as therapeutic agents. This chapter also includes the proposed biosynthesis of these compounds that relates them to their diterpene precursors. Chapter 2 describes the development of an aluminum chloride-mediated Dieckmann cyclization of dicarboxylic acids and acid chlorides that provides direct access to cyclic 2-alkyl-1,3-diones from acyclic starting materials. This strategy is showcased in the one-step synthesis of chiloglottone 3. These studies also revealed the unique properties of an aluminum chloride – nitromethane complex that is better suited for this transformation than individual Lewis acids. Chapter 3 describes our efforts to expand the scope of this transformation to include more substituted acid chloride substrates but instead observed the formation of 2-acetyl-1,3-diones. This led us to conduct 13C-labelling studies that established acid chlorides as formal carbon dianion linchpin reagents and led us to propose a revised mechanistic proposal for this transformation. Chapter 4 describes the evolution of our Dieckmann cyclization for the synthesis of atropurpuran and the arcutines. This chapter describes the synthetic design that enabled access to our key cyclic 1,3-dione intermediate and our ongoing efforts regarding the transformation of this advanced intermediate to the natural products.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/153500/1/amarmaly_1.pd