Abstract
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.
Highlights
Transition metals can catalyse the stereoselective synthesis of cyclic organic molecules in a highly atom-efficient process called cycloisomerization
Despite much research into transition metal-catalysed cycloisomerization[3,4], and reports where high enantioselectivity is achieved for the cyclization of prochiral substrates to enantioenriched products[5,6], this important field of synthetic methodology has neglected the development of enantiospecific diastereoselective transformations, where single enantiomer starting materials are subjected to asymmetric cycloisomerization to give specific diastereomer products[7,8,9,10]
This work demonstrates the powerful role of density functional level of theory (DFT) computations in understanding asymmetric catalysis, leading to quantitative computational-led design of new, highly selective ligands
Summary
Transition metals can catalyse the stereoselective synthesis of cyclic organic molecules in a highly atom-efficient process called cycloisomerization. Demand for higher efficiency, economy and selectivity in the synthesis of novel molecular scaffolds drives organic chemistry[1,2] In this context, cycloisomerizations represent ideal methods for the formation of cyclic organic molecules, as they can fulfil all of these criteria. We question whether a catalyst system optimized to achieve an enantioselective cyclization (1-2, Fig. 1b) can translate to a double stereodifferentiating setting (1-3 or epi-3, Fig. 1c), should the catalyst be required to overcome powerful substrate stereocontrol Intrinsic to these studies is a combined theoretical and experimental approach to optimize catalyst design[28,29,30], which in the event reveals an unexpected mechanistic pathway for rhodium-catalysed [5 þ 2] carbocyclizations (Fig. 1a). This work demonstrates the powerful role of density functional level of theory (DFT) computations in understanding asymmetric catalysis, leading to quantitative computational-led design of new, highly selective ligands
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