Stereoselective Assembly of Oxindole Alkaloid Natural Products

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With this Award, the Chemical Synthesis Program of the Division of Chemistry is supporting the research of Professor Brandon L. Ashfeld at the University of Notre Dame. The awarded proposal is focused on the development of new methods that address critical challenges in the synthesis of complex, high value molecular targets. The primary objective is to develop a suite of new tools that enable access to the core molecule scaffolds present in biologically relevant alkaloid natural products. The overarching strategy focuses on exploiting the reactivity of a single carbon component attainable from readily available precursors for accessing a diverse array of related targets. A key aspect of this proposal is the integration of research findings in the laboratory introduction of undergraduates and the training of graduate students in synthetic methods design and development. Undergraduate and graduate students are more likely to pursue advanced degrees in chemistry and careers in research and discovery when presented with a target-specific pedagogical approach toward chemical education. The incorporation of target-based instruction as it pertains to the molecular assembly of specific chemical functionality, rather than the traditional reaction-centered lab design prevalent today, is central to the broader impacts of this project.Despite the ubiquitous presence of 5-membered carbocycles and heterocycles in natural products chemistry and chemical biology, the number of reliable methods for the assembly of highly substituted rings with flexible site-specific functionalization capabilities is relatively limited. This project focuses on the development of new synthetic strategies toward alkaloid frameworks that address several key long-standing challenges in small molecule construction through the design and implementation of (4+1)- and (4+3)-cycloadditions. Specific objectives include the 1) the enantioselective synthesis of the spiropyrrolidine oxindole scaffold employing a formal (4+1)- cycloaddition; 2) enantioselective formal (4+3)-cycloaddition synthesis of the cycloheptane oxindole core of the welwitindolinone alkaloids; and 3) the stereoselective construction of spirocyclopentenone oxindoles by expanding the architectural diversity of available vinyl ketenes. Implementation of this design enables access to various polycyclic scaffolds bearing a central 5- or 7-membered ring. Toward that end, this project addresses challenges associated with the 1) convergent assembly of both 5- and 7-membered rings with the flexibility to provide carbo- and N-heterocyclic frameworks, 2) construction of a key stereogenic carbon with proximal functionality for subsequent manipulations, and 3) control of relative and absolute stereochemistry. The prevalence of these ring frameworks in translationally relevant targets highlights the scientific broader impacts of this work in chemical biology and therapeutics development. Additionally, the long-range significance of this study is its impact on C–C and C–N bond assembly in fields such as process flow chemistry and bioorthogonal reaction development. The synthetic methods developed form the basis for a cohesive pedagogical approach to laboratory instruction that will broadly impact STEM education efforts at all levels. By emphasizing target analysis, rather than reaction introduction, a cohesiveness between comprehension at the conceptual level and application to the synthesis of complex molecules is to be achieved.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.