Transition metals can catalyse the stereoselective synthesis of cyclic organic molecules in a highly atom-efficient process called cycloisomerization. Many diastereoselective (substrate stereocontrol), and enantioselective (catalyst stereocontrol) cycloisomerizations have been developed. However, asymmetric cycloisomerizations where a chiral catalyst specifies the stereochemical outcome of the cyclization of a single enantiomer substrate—regardless of its inherent preference—are unknown. Here we show how a combined theoretical and experimental approach enables the design of a highly reactive rhodium catalyst for the stereoselective cycloisomerization of ynamide-vinylcyclopropanes to [5.3.0]-azabicycles. We first establish highly diastereoselective cycloisomerizations using an achiral catalyst, and then explore phosphoramidite-complexed rhodium catalysts in the enantioselective variant, where theoretical investigations uncover an unexpected reaction pathway in which the electronic structure of the phosphoramidite dramatically influences reaction rate and enantioselectivity. A marked enhancement of both is observed using the optimal theory-designed ligand, which enables double stereodifferentiating cycloisomerizations in both matched and mismatched catalyst–substrate settings.

The first synthetic route to yndiamides,anovel class of double aza-substituted alkyne,h as been established by the copper(I)-catalyzed cross-coupling of 1,1-dibromoenamides with nitrogen nucleophiles.T he utility of these compounds is demonstrated in ar ange of transition-metal-catalyzed and acid-catalyzed transformations to affordawide variety of 1,2diamide functionalized products.

The cycloisomerization of enynes catalyzed by Pd(OAc) and bis-benzylidene ethylenediamine (bbeda) is a landmark methodology in transition-metal-catalyzed cycloisomerization. However, the mechanistic pathway by which this reaction proceeds has remained unclear for several decades. Here we describe mechanistic investigations into this reaction using enynamides, which deliver azacycles with high regio- and stereocontrol. Extensive H NMR spectroscopic studies and isotope effects support a palladium(II) hydride-mediated pathway and reveal crucial roles of bbeda, water, and the precise nature of the Pd(OAc) pre-catalyst. Computational studies support these mechanistic findings and lead to a clear picture of the origins of the high stereocontrol that can be achieved in this transformation, as well as suggesting a novel mechanism by which hydrometalation proceeds.

Non‐biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion‐mediated O‐alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O−H⋅⋅⋅NCO hydrogen bond. Upon O‐alkylation of the H‐bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H‐bond reduces the rotational barrier about the aryl–amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol −1 , thereby facilitating the observed dynamic kinetic resolution.

The first 1,4-arene migration from a carbon to a nitrogen center, induced by iminyl radicals generated from radical additions to vinyl azides, is reported. Two different modes of vinyl azide activation trigger this migration process, which offers a mild route for the synthesis of trifluoromethyl-or sulfonyl-substituted β-enamino ketones. Mechanistic studies reveal a dual role for the silver catalyst, and provide insight into the nature of the migration by demonstrating the positional influence of arene substituents on arene migratory aptitude. By in situ generation of the key migration substrate from readily available precursors, this method offers a new strategy for achieving remote C-to-N group migration, and more generally for the formal activation of C−C bonds.