In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Rodrigo Andrade of the Department of Chemistry at Temple University will apply novel synthetic methods toward the synthesis of various complex alkaloid natural products. While many methods exist for the preparation of complex alkaloids, there is a need for step-efficient, asymmetric methodology. Professor Andrade's research involves the discovery and development of novel methods to efficiently and selectively prepare complex natural products in an asymmetric manner, which is essential if they are to be employed as chemical probes in molecular biology. Professor Andrade's group recently reported a sequential one-pot bis-cyclization method that has enabled the concise syntheses of several Strychnos alkaloids; this method will be employed in the syntheses of novel Strychnos and Aspidosperma alkaloids.

Alkaloids have a rich history in medicine, as many synthetic and semi-synthetic drugs such as Naloxone are structural modifications of alkaloids. Therefore, more efficient synthetic approaches to this class of molecules will have significant impact on the pharmaceutical industry. Some of the methodology developed in this proposal is also applicable to other classes of molecules. Therefore, it will impact other areas of research (e.g., biochemical and agricultural sectors) in which the synthesis of these molecules is needed. In terms of educational impacts, this project will provide excellent training of students, including those from groups historically underrepresented in the sciences.

Project Report

A. Intellectual Merit The overall research goal of the project was to synthesize novel, complex indole alkaloids belonging to the Aspidosperma and Strychnos and families in a catalytic asymmetric manner using novel chemistry. In 2009, the PI discovered a novel one-pot bis-cyclization method for concisely assembling the ABCE tetracyclic framework of Strychnos alkaloids. In 2010, this method was utilized in the concise total syntheses of Strychnos alkaloids akuammicine and strychnine. Recently, this method was expanded to include the Aspidosperma family of indole alkaloids. In 2010, Luo and co-workers isolated (-)-melotenine A, a unique rearranged Aspidosperma alkaloid from Melodinus tenuicaudatus. This natural product represents an excellent opportunity to showcase the utility of our bis-cyclization approach within the Aspidosperma family of indole alkaloids Accordingly, our first objective was to execute the first total asymmetric synthesis of (-)-melotenine A. To that end, we optimized our bis-cyclization method and employed additional vinylogous aldol and intramolecular vinyl iodide/ketone additions as key steps. While working on melotenine, we were inspired to try and access this unique framework in a highly step-efficient manner. To that end, we developed a new method – the domino Michael/Mannich reaction – using chiral N-sulfinyl metallodienamines. These reagents had not been previously studies. To our delight, we were able to apply this method to the concise asymmetric total syntheses of (-)-aspidospermidine, (-)-vincadifformine, and (-)-tabersonine from indole-3-carboxaldehyde. In 2013, we published the first total synthesis of that natural product. Later that year, Kam and co-workers isolated the bis-Strychnos alkaloids (+)-leucoridines A-D from Leuconotis griffithii, which he hypothesized is derived from the coupling of two monomeric units. As our second objective, we recently completed the first total asymmetric syntheses of (+)-leucoridines A and C using the biomimetic coupling strategy featuring an optimized acid-promoted coupling of two monomeric units. Finally, in 2006 Frédérich and co-workers isolated several bis-Strychnos alkaloids called sungucines. The semisyntheses of these congeners from cheap, commercially available strychnine comprises the third objective of the proposal. We also recently accomplished this synthesis, along with that of (-)-strychnogucine B and (-)-isosungucine. The long-term goal of the PI’s laboratory is to develop novel synthetic methods, apply them toward the concise assembly of complex alkaloids, and understand the mechanistic underpinnings of all processes involved. This final report chronicles our efforts to that goal. B. Broader Impacts The proposed research plan will advance knowledge in the field of synthetic organic chemistry (i.e., chemical synthesis). These targets will test the efficiency of the PI’s novel methodology. The concise approaches detailed in the proposal could be applied to a host of Strychnos and Aspidosperma alkaloids to serve as chemical probes. That the routes are asymmetric enables such an endeavor. A central objective of the proposed plan is the training of graduate students and undergraduates. These individuals represent the future of the scientific enterprise and as such, investment in the proper and effective training thereof is a top priority. The rigors of synthetic organic chemistry offer unparalleled training to the practitioner. Temple University boasts one of the most culturally diverse urban campuses in the United States; as such, it is an excellent source of underrepresented groups in the sciences. Finally, our findings will be presented at local and national conferences and meetings. The results are expected to impact those working in the fields of chemical and total synthesis, biochemistry and chemical biology. C. Summary of Findings In this funding period, the PI’s laboratory has developed new tools for the preparation of complex nitrogen-containing natural products (NP’s). We applied those tools to the synthesis of nine complex NP’s, each of which has unique biological activity. With access to these compounds, scientists can also unravel the mechanism of action, which will help in the identification (diagnosis) and treatment (medicines) of various disease states. NP’s have played a central role in the development of chemistry, biology, and medicine. Over half of all medicines are either natural products or derivatives thereof. Accordingly, new tools that allow man to prepare these complicated structures of paramount importance in faster, more efficient ways drives the cost of production down, which is transferred to the consumer (i.e., patient). The funding of this research project successfully delivered new tools for making complex molecules with great relevance to mankind.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Tingyu Li
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Temple University
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