Asymmetric Formal [4+1]-Cycloadditions for the Stereoselective Assembly of Quaternary Stereogenic Centers

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The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Brandon L. Ashfeld. Professor Ashfeld is a faculty member in the Department of Chemistry and Biochemistry at the University of Notre Dame, and is developing new synthetic methods that enable construction of functionalized heterocyclic and carbocyclic frameworks that contain very difficult to synthesize tetrasubstituted carbons. Cyclic systems that contain tetrasubstituted (or quaternary) carbons are found in a great number of molecules used in biological and materials science settings. Yet in spite of their importance, these ring systems remain difficult to synthesize, especially if they need to be constructed as a single "right-handed" or left-handed" mirror image in order to control molecular interactions with a biological system. To address this issue, Professor Ashfeld and his students are developing new methods for constructing both the hetero- and carbocyclic systems and the highly hindered quaternary carbons they contain. These methods take advantage of a transition metal catalyzed formal [4+1]-cycloaddition between a single carbon unit and a polarized four atom substrate. The catalyst used is chiral so that the reaction affords predominately one mirror image of the product. The project outcomes are broadly impacting the disciplines of synthetic and physical organic, organometallic, medicinal, and materials chemistry both in terms of the methods developed and the products generated. The scientific goals of the project integrate seamlessly with the education/outreach pursuits through the implementation of a target-based pedagogical philosophy toward STEM education at the secondary and post-secondary levels. These educational efforts are being complimented by Professor Ashfeld's contributions to the Upward Bound College Preparatory program in South Bend Indiana that serve to extend the program's reach beyond his labs to the larger community.Quaternary stereogenic carbons and carbo- and heterocycles are pervasive architectures across numerous facets of academic and industrial chemical research. Despite the ubiquitous presence of 5-membered carbocycles and heterocycles in medicinal chemistry (e.g., CNS drugs, analgesics, antibiotics, etc.) and materials science (e.g., ionic liquids, high energy materials, etc.), the number of reliable methods for the assembly of highly substituted rings with flexible site-specific functionalization capabilities is relatively limited. Additionally, the synthesis of quaternary carbon centers is far from trivial, and to do so with control of absolute stereochemistry remains a significant obstacle in target-directed synthesis. Using the biologically active spirooxindole alkaloids as a motivating template for design, this project concurrently addresses these challenges through the development of a transition metal-catalyzed, formal [4+1]-cycloaddition for the fragment coupling of a diazo compound with a vinyl ketene to access cyclopentenones bearing a neighboring quaternary center, and vinyl isocyanates to construct the N-heterocyclic counterpart. By employing a well-defined chiral ligand-metal complex, assembly of the quaternary ring stereogenic carbon in a stereocontrolled fashion while acting as a point of spiro-attachment en route to numerous oxindole alkaloids, is tenable. Due to the chemoselective nature of the transition metal catalyst and relatively mild reaction conditions, this retrosynthetic disconnect is broadly applicable to a diverse array of synthetic targets. Completion of this study will ultimately lead to improved synthetic efficiency toward these important molecular scaffolds, and lay the keystone for long term significance in stereoselective quaternary carbon and carbo/heterocycle formation. The educational plan will integrate our findings in the training of graduate students in their approach toward synthesis, and the introduction of undergraduates to synthetic methods in laboratory offerings. The incorporation of a target-based approach toward molecule construction, such as quaternary carbon and heterocycle synthesis with tangible applications (i.e. pharmacophores), rather than the traditional reaction-centered lab design prevalent today, is an immediate goal. Graduate and undergraduates alike will gain a better appreciation for reaction design, and the discovery of new chemical reactivity, if their focus is on a series of specified target functionalities that are translational in nature.