Improving, Controlling, and Applying 4π-Electrocyclizations of N-Vinylnitrones

N-Heterocycles comprise 60% of small-molecule drugs and exhibit a variety of remarkable bioactive properties. Strained N-heterocycles with 3- and 4-membered rings have been highly sought after as new therapeutics due to their rigid structures and polarity but are not as extensively studied as 5- and 6- membered ring examples because of their synthetic challenges. New methods for preparing 4-membered ring heterocyclic compounds that are tolerant of a wide range of functional groups are valuable and of high interest. In this work, densely functionalized azetidine nitrones have been synthesized from N-vinylnitrones through a 4π-electrocyclization. These conrotatory 4-π-4-atom electrocyclizations are unusual due to the ring-strain installed in the forward direction and are synthetically valuable for the diastereoselective preparation of partially unsaturated azetidines that can be used for divergent derivatization. To further develop this method, mechanistic studies were used to develop a fundamental understanding of the substituent and solvent effects in these transformations. A systematic series of Hammett, Eyring, and relative rate studies were undertaken with results demonstrating the utility of these trends in understanding the process and broadening the method. Mechanistic investigations, including Hammett studies, solvent dependent Eyring studies, and solvent isotope effects, provided insight into the steric and electronic factors that control these electrocyclizations and identified trends that were used to advance this approach towards the rapid synthesis of complex azetidines. The second part of this work focuses on the development of a catalytic asymmetric electrocyclization for the synthesis of azetidine nitrones through torquoselective control of C–C bond formation. Catalyst screening was performed using high-throughput experimentation (HTE) and a Pd(II) complex was identified that can control the direction of conrotatory rotation. Further optimization determined general conditions for the catalytic asymmetric synthesis of azetidine nitrones and the scope of this transformation was explored. Complementary computational modelling allowed for a better understanding and support of the torquoselectivity observed. Overall, this work provides new ways to access chiral non-racemic azetidines with imbedded functionality for further derivatization.