New Synthetic Opportunities with N-Alkenylnitrones and N,O-Dialkenylhydroxylamines

With support from the Chemical Mechanism, Function, and Properties Program in the Division of Chemistry, a research team at the University of Illinois at Chicago are developing new reactions to rapidly assemble novel molecules through unconventional strategies using N-alkenylnitrones and N,O-dialkenylhydroxylamines as reactive intermediates. The rearrangement reactivity of these intermediates is being controlled to form more complex molecules with defined three-dimensional structure. Simple modular routes to generate N-alkenylnitrones and N,O-dialkenylhydroxylamines from readily available reagents are being used to facilitate these activities. This work is targeting improved synthetic efficiency to expand chemical space. Improvements in this area are necessary to support the discovery, accessibility, and study of biologically active molecules, as well as the development of new materials. These activities are also providing training for graduate and undergraduate students to become successful members of the chemical workforce and lowering barriers to students engaging in undergraduate research and considering chemistry career paths. Improving efficiency to enable rapid access to new molecular targets and expanding chemical space to include new molecular architectures remain two critical needs in organic synthesis to support demands for new compounds with novel properties for medicinal and material applications. The unique reactivity of N-alkenylnitrones and N,O-dialkenylhydroxylamines is being developed to address these goals by providing alternative solutions to synthetic challenges and improving the fundamental understanding of these versatile and unusual synthons to expand the synthetic toolbox of pericyclic and cascade reactions. More specifically, stereocontrol of the new C–C bond forming reactions that these synthetic intermediates undergo is being investigated through the development of: (i) catalytic asymmetric 4pi- and 6pi-electrocyclizations of N-alkenylnitrones for the synthesis of enantioenriched azetidine nitrones and oxazines, (ii) catalytic asymmetric sigmatropic rearrangements of N-alkenylisoxazolines for the synthesis of enantioenriched 1-pyrrolines, and (iii) stereoselective nitrone-templated sigmatropic rearrangements and C–H bond insertion reactions for the synthesis of 1,4-dicarbonyl compounds. These activities are training students in chemical experimentation and a series of events are engaging undergraduates in considering the merits of research experiences and opportunities available in chemistry career paths. 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.