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.

Public Health Relevance

Nitrogen-containing molecules are ubiquitous in nature and have undergone intense investigation for over a century, resulting in the development of numerous methods in organic chemistry that form the basis of current drug discovery. This proposal aims to establish new methods in C-H and N-H functionalization to access a variety of nitrogen-containing frameworks in a practical manner. These methods will benefit scientists from both academic and industrial settings in medicinal chemistry, and the synthesized molecules will be subjected to a panel of cancer cell lines and diseases to probe for biological activity.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Rosen, Brandon R; Werner, Erik W; O'Brien, Alexander G et al. (2014) Total synthesis of dixiamycin B by electrochemical oxidation. J Am Chem Soc 136:5571-4
Rodriguez, Rodrigo A; Barrios Steed, Danielle; Kawamata, Yu et al. (2014) Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology. J Am Chem Soc 136:15403-13
Ma, Zhiqiang; Wang, Xiaolei; Wang, Xiao et al. (2014) Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence. Science 346:219-24
Rodriguez, Rodrigo A; Pan, Chung-Mao; Yabe, Yuki et al. (2014) Palau'chlor: a practical and reactive chlorinating reagent. J Am Chem Soc 136:6908-11
O'Hara, Fionn; Baxter, Ryan D; O'Brien, Alexander G et al. (2013) Preparation and purification of zinc sulfinate reagents for drug discovery. Nat Protoc 8:1042-7
Zhou, Qianghui; Ruffoni, Alessandro; Gianatassio, Ryan et al. (2013) Direct synthesis of fluorinated heteroarylether bioisosteres. Angew Chem Int Ed Engl 52:3949-52
O'Hara, Fionn; Blackmond, Donna G; Baran, Phil S (2013) Radical-based regioselective C-H functionalization of electron-deficient heteroarenes: scope, tunability, and predictability. J Am Chem Soc 135:12122-34
Kock, Matthias; Schmidt, Gesine; Seiple, Ian B et al. (2012) Configurational analysis of tetracyclic dimeric pyrrole-imidazole alkaloids using a floating chirality approach. J Nat Prod 75:127-30
Mendoza, Abraham; Ishihara, Yoshihiro; Baran, Phil S (2012) Scalable enantioselective total synthesis of taxanes. Nat Chem 4:21-5
Fujiwara, Yuta; Dixon, Janice A; Rodriguez, Rodrigo A et al. (2012) A new reagent for direct difluoromethylation. J Am Chem Soc 134:1494-7

Showing the most recent 10 out of 30 publications