Synthesis of Pyrrole-Imidazole Alkaloids

Scripps Research Institute, The, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The isolation, structural analysis and laboratory synthesis of complex natural products have traditionally formed the core of organic chemistry. Lessons learned from these endeavors have culminated in an immense knowledge of chemical reactions, from which entire industries of medicinal chemistry, agrochemistry, food chemistry, fragrance chemistry, and polymer chemistry have originated. While the practice of total synthesis has been vital to both the development and practicality assessment of new methods, recent chemistry groups often build their research programs solely around developing methods without a specific target in mind. In line with this current environment, this proposal primarily seeks to develop practical C-H and N-H functionalization reactions, but keeping with the spirit of targeted synthesis, the total synthesis of dimeric and trimeric alkaloid natural products will be accomplished. Specifically, methods in aromatic chlorination, guanidine C-H cyclization and electrochemical dimerization will be developed for the overarching goal of broad utility in medicinal chemistry, but with the added aim of synthesizing pyrrole-imidazole alkaloids, indole-imidazole (indole-guanidine) alkaloids and N-N-containing dimeric alkaloids. This proposal is organized into three independent parts that are unified under the theme of methodology development for alkaloid synthesis. The first section draws inspiration from a chlorospirocyclization reaction from our published axinellamine synthesis to develop an efficient and regioselective aromatic chlorination reaction. This will be applied to an optimized synthesis of the core structure of the pyrrole-imidazole alkaloid family of natural products, and specificall for the synthesis of recently isolated members of the family, donnazoles A and B. The second part of the proposal outlines the development of a C-H guanidinylation reaction for cyclic guanidine synthesis. This will be a key transformation in the total synthesis of the araiosamine family of natural products, which are trimeric indole-imidazole alkaloids. Lastly, the third sectio argues that electrochemistry can be a fundamental aid to organic synthesis, wherein a method for N-H functionalization to generate N-N bonds is presented. This opportunity for invention has long been obscured by a certain fear of electrochemistry, which we hope to dispel by presenting a scalable synthesis of complex dimeric alkaloids. While these three objectives will be investigated in parallel, they will all contribute in establishing key methods for the synthesis of complex nitrogen-containing compounds, which will accelerate discovery in medicinal chemistry and other chemical and scientific disciplines. Furthermore, we have secured numerous collaborators with both academic and industrial scientists to examine the medicinal properties of the natural products that will be accessed in meaningful amounts.