Enantioselective [4 + 2] Cycloaddition Enabled by Sequential Photoinduced [1,3]-Silyl Migration and Isothiourea Catalysis

Abstract

Chiral isothioureas represent a highly efficient class of organocatalysts, which can activate substrates such as anhydrides, esters, and ketenes to generate C(1)-ammonium enolate intermediates, and have been widely used in the construction of chiral heterocyclic compounds and biologically active molecules. However, the accessible C(1)-ammonium enolate intermediates are largely limited to those bearing hydrogen, alkyl, or aryl substituents. The corresponding oxygen-substituted variants, which would provide valuable access to α-hydroxy ketone motifs, remain inaccessible due to the scarcity of suitable starting materials. α-Ketoacylsilanes can undergo photoinduced [1,3]-silyl migration to in situ generate siloxyketenes, providing a new strategy for the construction of oxy-substituted ketene intermediates. Herein, we developed an enantioselective [4+2] cycloaddition reaction combining sequential photoinduced [1,3]-silyl migration and isothiourea catalysis. Under the irradiation of blue LEDs at room temperature, α-ketoacylsilanes and acyclic azadienes were used as readily available substrates, with chiral HyperBTM as the optimal catalyst to realize highly stereoselective cycloaddition. The reaction features mild reaction conditions, operational simplicity, a broad substrate scope, and generates structurally diverse chiral dihydropyridinone derivatives in good yields (up to 88%) with high enantioselectivities (up to 99% ee). This transition-metal-free methodology not only expands the scope of C(1)-ammonium enolates but also provides a new and reliable platform for the construction of δ-lactam scaffolds bearing chiral tertiary alcohol motifs.

Keywords

[4 + 2] Cycloaddition / Isothiourea / Enantioselective / Photoinduced / [1,3]-Silyl migration / α-Ketoacylsilanes / Methodology and reactions / Azadienes

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