Strategies for the Syntheses of Complex Molecules

This thesis highlights a multitude of projects all with the goal of synthesizing complex molecules, either to probe their biological activity or as a proof-of-concept for novel synthetic strategies. The first of these projects discussed is the development of novel drug analogues based on the isocyanoterpene family of natural products. The first compound is an artemisinin-derivative with an installed isocyanide functionality. With the core structure of artemisinin and the motif resembling isocyanoterpenes, this drug was developed to fight malaria by employing multiple mechanisms of actions. The second part of this project is the syntheses of a pair of diastereomers, MK-109 and MK-110, whose promising bioactivities are still under investigation by collaborating groups. The synthetic efforts produced a viable convergent route to afford both compounds in appreciable scale for biological assays. The syntheses of these analogues afforded the desired compounds in appreciable scale and in an efficient manner, allowing for deeper investigations into their bioactivities and pharmacokinetics. The second project discussed over three chapters of this thesis is the Vanderwal lab’s efforts toward the synthesis of the curvulamine family of natural products. These dipyrrole alkaloids were targeted with the strategy of installing the electron-rich pyrroles late in the synthesis, which led to a series of investigations into novel pyrrole annulation reactions. Efforts toward the bicyclic curvulamides resulted in the total synthesis of two other natural products in the most concise manner reported. Efforts toward synthesizing the tetracyclic curvulamines involved a radical bicyclization strategy and a strategy invoking enolate alkenylation chemistry. Although the syntheses of the targeted natural products were not achieved, our efforts did result in a greater understanding of the application of modern methodologies to complex systems. Our ongoing efforts toward the synthesis of the arcutine family of natural products our focused on a convergent route to arcutinidine to avoid the pitfalls noted in previously reported syntheses. The development of a route to two fragments of the natural product was achieved and optimized to be highly scalable. Investigations of converging these fragments are currently underway and may act as a proof-of-concept for a very concise synthesis of the arcuitines. The efforts detailed within highlight the challenges of developing a synthesis on large scale and the problem-solving required to overcome these challenges. The final project of this thesis is the use of iron-tricarbonyl complexation to protected relay-prone dienes when subjected to alkene metathesis conditions. This novel strategy allows for selective dienophile metathesis in the presence of a diene to synthesize novel Diels-Alder cycloadducts. These efforts led to a focus on the development of transannular Diels-Alder cycloaddition precursors using this method, which resulted in a novel method of synthesizing diene dimers. These new discoveries in the application of iron-diene complexes have opened a path for multiple future projects, including novel methods and total syntheses