Catalytic Asymmetric Route to Enantioenriched Cyclic Allenes and a Nickel-catalyzed Dynamic Kinetic Resolution of Cyclic Allenes

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Highly functionalized heterocycles are important motifs in pharmaceuticals. Although there have been many noteworthy advances in synthetic organic methodologies, the efficient synthesis of enantioenriched heterocycles remains an ongoing challenge in the field. The primary goal of this proposal is to access enantioenriched compounds utilizing heterocyclic allene intermediates. Cyclic allenes have been avoided historically due to their high reactivity. However, the proposed research seeks to harness cyclic allenes for the efficient construction of complex scaffolds. Moreover, the inherent chirality of cyclic allenes opens opportunities to access enantioenriched adducts. The manipulation of heterocyclic allenes in a controlled manner would offer new tactics for the synthesis of enantioenriched, complex heterocycles. This proposal includes two strategies that utilize heterocyclic allenes to generate enantioenriched products. In Aim 1, an asymmetric, catalytic synthesis of oxacyclic allene precursors will be optimized to ultimately enable facile access to enantioenriched oxacyclic allenes. An investigation into the ability to transfer stereochemical information from the allene precursor all the way to enantioenriched cycloadducts will be described. The studies in Aim 2 will allow access to enantioenriched heterocycles via a transition metal- catalyzed dynamic kinetic resolution of heterocyclic allenes. Optimization of the transformation and exploration of the substrate scope is described. These studies would ultimately demonstrate the utility of strained cyclic allenes in asymmetric synthesis.