This research program explores both the synthesis of novel molecules and methodology studies. These novel natural products include gliovirin, ceanothine D, and the marinopyrroles. The methodology studies will involve mechanistic studies and further applications of the trisubstituted aziridine ring opening reactions. Gliovirin is known for its biological activity but it has never been synthesized. The proposed synthetic strategy will explore a furan Diels-Alder reaction that could prove applicable to other structurally similar compounds. Ceanothine D is a unique cyclopeptide alkaloid whose absolute configuration remains unknown. Two approaches are designed to synthesize this compound. The first will investigate a novel strategy using the aziridine opening methodology previously developed. The second approach will involve a more traditional synthetic strategy. The absolute configuration of the product will be established as well. Investigation of the trisubstituted aziridine ring opening reactions will continue. The reaction has shown utility in the stereoselective synthesis of quaternary centers. Application of different nucleophiles to these aziridines will elucidate the reaction mechanism and afford chiral synthons for other synthetic endeavors. The marinopyrroles are a class of densely halogenated natural products. These antimicrobial active bis-pyrrole structures exhibit axial chirality and tetrachlorination of the bis-pyrrole core. The proposed program will develop synthetic strategies for these novel natural products, expand current methodological studies, and work to educate students for the continued advancement of organic synthesis.
With the support of this award from the Chemical Synthesis Program, Professor Madeleine Joullié of the Department of Chemistry at the University of Pennsylvania is exploring the synthesis and properties of molecules that exhibit promising biological activity. Efficient and reliable methods for their synthesis will enable the scientific community to understand the bioactivity of related natural or synthetic products. These bioactive molecules could provide new leads for anticancer and antibiotic drug discovery, influencing the fields of biology, chemistry and pharmacology. Gliovirin, a novel compound, presents a challenging target for synthesis and possesses significant bioactivity. A total synthesis of this natural product will establish reliable reactions to construct complex molecular structures as well as provide material for further biological evaluation. Ceanothine D was isolated from a flowering member of the Buckthorn family indigenous to eastern and central North America. The leaves from the plant were used as a substitute for tea during the Civil War and the brew was reputed to have hypotensive action. The medicinal use of the plant warrants an investigation into the chemicals responsible for its therapeutic effects. Its historical background and potential biological activity makes ceanothine D an interesting target. The marinopyrroles are antimicrobial structures that represent challenging synthetic targets and show a novel biological mechanism in the treatment of MRSA (drug-resistant staph infection), a clinically and sociologically relevant disease state. Scientific education of students and the general population is important to the future of society. Basic chemical research provides a platform for scientific education. The proposed program provides a fertile ground for basic research leading to advanced research areas. The proposed areas of interest will provide knowledge from which new scientific breakthroughs may occur. More importantly, the proposed studies will contribute to the education and future of many students including women and minorities, who have benefited from previous NSF Awards.
The goal of this research proposal was to develop efficient strategies for the synthesis of natural products that have unusual structural features requiring new methodology. Our research aims were the following: 1. Advancement of the synthetic utility of amino acids through the formation of novel chiral building blocks. 2. Exploration of various methods for macrocyclization to form medium and large rings found in natural products. 3. Investigation of the ring opening mechanism of tri-substituted aziridines. 4. Development of alternates ways to obtain roquefortine C and related biologically active metabolites. Findings The chiral building blocks were instrumental in preparing bicyclic structures derived from phenylalanine, tyrosine, and tryptophan that appeared to fit the basic pharmacophore model for the dopaminergic activity and were tested in a variety of neurotransmitter assays. They were found to possess only weak activity but could serve as a lead structure for further development. Ceanothine D is a metabolite of Ceanothus americanus also known as New Jersey tea plant or red root tea plant. It was used as a tea substitute during the Civil War and used to treat a variety of ailments including blood coagulation and blood pressure. We have synthesized its macrocycle using a novel synthetic approach and will be able to assess its stereochemistry. Aziridines are synthetically useful intermediates due to their highly strained ring system that allows for a wide range of reactivity via ring-opening reactions. However, di- and trisubstituted aziridines do not always exhibit predictable regioselectivity: 2,2,3-Tri-substituted aziridines were found to undergo ring opening at the more substituted carbon under mild basic conditions. However, the reason for the formation of the more sterically encumbered product had never been examined. To investigate the reasons for this uncommon behavior we varied the experimental conditions, examined X-ray structures, and designed a computational model to calculate ring opening transition state energies. We reported the first synthesis of roquefortine C by implementation of a novel elimination strategy to construct the thermodynamically unstable E-dehydrohistidine moiety that is typical of its structure and carried out molecular modeling studies to explain the instability of this compound. However, this research did not solve the availability of the compound, which was needed for investigation of its biomimetic pathway to other alkaloids, never previously synthesized. Commercial availability was not a viable option, since only small quantities are available at high cost. As the goal was the generation of advanced intermediates, we searched for other alternatives to obtain sufficient quantities for further study. After much investigation, we were able to harvest synthetically useful amounts of roquefortine C by means of fermentation from Penicillia, allowing us to efficiently further explore its related biosynthetic pathway. Broad Impact The focus of the program was to integrate biosynthetic modifications with medicinal chemistry to create compounds that would be starting sources for new drug discoveries. Multi-steps syntheses should be short and efficient and practical. New bioactive fungal metabolites offer structure and activity diversity and drug potential to discover novel bioactive natural products. They could be produced by fermentation to obtain gram quantities of complex molecules that could be synthetically manipulated in a number of ways. The aims would be diverse: they could be used to investigate their biosynthetic pathways; they could be modified chemically to eliminate or modify their activities; they could produce novel structures and new enzymes to accomplish selective transformations. In addition, they would eliminate long, protracted chemical syntheses and become a proof of concept for different ways to support green chemistry. Other contributions The program has contributed to human development of many young people that went on to diverse professions by teaching them ethics and professional behavior. They learned to present their work to an audience, to solve problems and be prepared for further study and professional endeavors. Contributions beyond science were made by training individuals that will use critical thinking in all areas of human life whether it is politics, sociology, or education. Publications 1. Kelley, B. T. and Joullié, M. M., Org. Lett., 2010, 12, 4244-4247. 2. Lee, J., Berritt, S., Prier, C. K., and Joullié, M. M., Org. Lett., 2011, 13, 1083–1085. 3. Kelley, B. T. and Joullié, M. M., Tetrahedron Asymmetry, 2013, 24, 1233-1239. 4. Kelley, B. T., Carroll, P., and Joullié, M. M., J. Am. Chem. Soc., 2014, submitted. (Title: A possible reason for the unusual regioselectivity in nucleophilic ring opening of tri-substituted aziridines under mild basic conditions)
