Higher-Order Cycloisomerisations of Enynamides

Abstract:: This thesis describes the development of a novel transformation of ynamides, and addresses more general questions of asymmetric cycloisomerisation. The rhodiumcatalysed [5+2] cycloisomerisation of ynamide vinylcyclopropanes A1 to [5.3.0]- heterobicycles A2 is established (Scheme i). We design a versatile substrate synthesis, which allows the preparation of diversely substituted enynamide substrates. Under achiral rhodium catalysis, the extent of substrate diastereo- and regioselectivity is investigated.

The reaction is rendered asymmetric with the use of chiral phosphoramidite ligands; where a mechanistic hypothesis for stereoselectivity leads to the development of a powerful catalyst system for the preparation of enantioenriched A3. A theoretical reaction analysis elucidates the mechanistic pathway, and gives an energetic rationale for our model of ligand stereoinduction. Our asymmetric catalyst system is applied to the [5+2] cycloisomerisation of chiral substrates in double stereodifferentiating transformations, where it is possible to synthesise previously inaccessible diastereomers of product A4.

Related item:: Computational ligand design in enantio- and diastereoselective ynamide [5+2] cycloisomerization
Description:: 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.

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Thesis