Fluxional Nitrogen in Play: A Strategy for Enhancing Stereoselectivity in Asymmetric Catalysis

ConspectusPyramidal inversion at sp³ nitrogen centers is a generally rapid process with low energy barriers in the absence of geometric constraints or adjacent electronegative atoms. In an N-stereogenic amine, rapid inversion at nitrogen results in a state of dynamic or "fluxional" chirality at the nitrogen center, with no long-lived stereochemical configuration. To take advantage of N-centered chirality for stereoselective synthesis, we established a unique strategy that harnesses fluxional chirality at nitrogen in enantioselective catalysis. In our research, we employed substituted pyrazolidinones and 2-pyrazolines─simple structural units containing fluxionally chiral nitrogen centers─as stereocontrol elements in templates, ligands, organocatalysts, and additives. The fluxional chirality functions not alone but rather in concert with a source of static chirality: the interaction of fluxional chirality with static chirality can enhance stereoinduction. This is a "best of both worlds" approach that enables the use of formally achiral structural units to amplify stereoselectivity and circumvents match-mismatch issues that can arise when two sources of static chirality are used in combination to attain higher enantioselectivity.We investigated the impact of fluxional chirality in a variety of catalytic transformations. Across many different catalytic systems, enantioselectivity generally correlated with the size of the fluxional substituent on the stereogenic nitrogen, consistent with a role for fluxional chirality in enantioselectivity enhancement. The fluxionally chiral reaction components provided other benefits in individual transformations. Using pyrazolidinone templates, we developed chiral Lewis acid catalyzed Diels-Alder reactions, dipolar cycloadditions, and conjugate additions that proceeded with high enantioselectivities, in many cases at moderate temperatures (room temperature or 0 °C). The templates allowed us to achieve control over rotamer geometry, endo/exo selectivity, and regioselectivity in relevant contexts. Expanding the scope of our strategy, we developed additional enantioselective transformations involving ligands, organocatalysts, and additives with fluxional chirality. We synthesized ligands with varied donor atoms for metal coordination and applied these in Lewis acid catalyzed Diels-Alder reactions, diethylzinc additions, and palladium-catalyzed allylic alkylations. In our work on organocatalysts, 4-(dimethylamino)pyridine-based catalysts provided high selectivities in reactions including kinetic resolutions and dynamic kinetic resolutions of biaryl compounds, and thiourea catalysts promoted highly enantioselective conjugate additions to nitroalkenes. Pioneering a novel application of additives in asymmetric catalysis, we employed pyrazolidinone-based additives with a stereogenic nitrogen to achieve enantioselectivity enhancements in Lewis acid catalyzed cycloadditions─an attractive approach using simply a small, achiral molecule to amplify stereoinduction.These asymmetric methods encompass significant variation in modes of catalysis, mechanistic pathways, means of enantioinduction, and spatial separation between static and fluxional chirality. Together, our results validate N-centered fluxional chirality as a useful phenomenon with significant versatility in asymmetric synthesis. With this foundation, the use of fluxional chirality at nitrogen is poised to become a more widely implemented strategy with new applications in enantioselective catalysis.