Cascade Cyclizations for Small Molecule Synthesis

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The Chemical Synthesis Program of the NSF Chemistry Division supports the research of Professor Alison Frontier in the Department of Chemistry at the University of Rochester. Professor Frontier and her students are developing highly efficient cyclization reactions which are capable of creating compact polycyclic molecules that are difficult to prepare using other synthetic strategies. These chemical methods enable rapid synthesis of complex natural and non-natural bioactive molecules, especially small molecules with properties demonstrated to be valuable in drug discovery efforts. With respect to educational activities, development continues for an educational website ("Not Voodoo"), which is designed as a resource for students beginning independent research in an organic chemistry laboratory. Professor Frontier enriches the site with new resources, and also enhance the experience of visitors by expanding functionality. The research program involves the study of novel cationic reactivity and the development of efficient and green synthetic methods. The projects focus on multistep reaction cascades that merge nucleophilic reactivity with cationic electrocyclic reactions, and allow the execution of highly stereocontrolled cyclizations. This research is leading to a richer understanding of redox cyclizations which are initiated by hydride shift, cyclizations coupled to pyridine and furan dearomatization, and the execution of higher-order electrocyclizations, which are virtually unknown reactions. New strategies for achieving enantioselective electrocyclization are also being evaluated. The proposed research is directed toward both exploring new reactivity and the development of efficient, diastereo- and enantioselective methods that rapidly transform acyclic systems into bridged, fused, or spirocyclic small molecules. The synthetic strategies are efficient and modular, typically carried out in an environmentally friendly fashion. Small molecule targets of this research have desirable physicochemical properties and occupy unique chemical space; these features often correlate to bioactivity and meet stated needs for improving the quality of compound collections for use in drug discovery programs. Efforts are also focused on further development of the Not Voodoo website, a resource that serves hundreds of organic experimental chemists each day.