Exploiting Catalyst-Controlled Mechanistic Divergency in Cycloaddition Approaches to Oxindole Alkaloid Synthesis

About This Grant

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Brandon Ashfeld of Notre Dame University is studying the development of new chemical reactions that address critical challenges in the synthesis of complex, high value molecular targets. New synthetic tools are being evaluated based on a universal reaction design concept that enables access to functionalized oxindoles, a type of structure present in a variety of biologically relevant molecules. The new synthetic tools employ selective transition-metal catalyzed reactions to make a variety of distinct changes to a single molecular intermediate in the presence of simple building blocks. While advancing methods for organic synthesis, this research program is also being used to train graduate students in synthetic chemistry and to engage undergraduate students in teaching labs through a molecular-target-specific pedagogical approach. These activities are being used to encourage students to consider careers in research and discovery. Despite the ubiquitous presence of cycloannulated indole and oxindoles frameworks in medicinal chemistry and materials science, the number of reliable, efficient methods for diversifying these building blocks with flexible site-specific functionalization capabilities is relatively limited. Using these synthetic targets as motivating templates for reaction design, Prof. Ashfeld and his reaction team are using the difference in reactivity between PdII- and RhII-carbenoids to selectively favor [3+1]-, [3+2+1]-, and [4+3]-cycloadditions for the construction of key alkaloid frameworks. A central diazooxindole intermediate is being divergently functionalized using these methods and fundamental reactivity lessons learned about being used to expand the reactivity scope to the asymmetric synthesis of cyclobutenes, pyrans, and complex indole ring-systems, including the total synthesis of N-methylwelwitindolinone C isothiocyanate. The synthetic methods being developed also form the basis for a cohesive pedagogical approach toward laboratory instruction that will broadly impact STEM education efforts at all levels. By emphasizing target analysis, rather than traditional reaction introduction, a cohesiveness between comprehension at the conceptual level and application to the synthesis of complex molecules is being emphasized to encourage students to continue studies in STEM fields. 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.