Single-Electron Oxidation-Initiated Enantioselective Hydrosulfonylation of Olefins Enabled by Photoenzymatic Catalysis.

Controlling the enantioselectivity of hydrogen atom transfer (HAT) reactions has been a long-standing synthetic challenge. While recent advances on photoenzymatic catalysis have demonstrated the great potential of non-natural photoenzymes, all of the transformations are initiated by single-electron reduction of the substrate, with only one notable exception. Herein, we report an oxidation-initiated photoenzymatic enantioselective hydrosulfonylation of olefins using a novel mutant of gluconobacter ene-reductase (GluER-W100F-W342F). Compared to known photoenzymatic systems, our approach does not rely on the formation of an electron donor-acceptor complex between the substrates and enzyme cofactor and simplifies the reaction system by obviating the addition of a cofactor regeneration mixture. More importantly, the GluER variant exhibits high reactivity and enantioselectivity and a broad substrate scope. Mechanistic studies support the proposed oxidation-initiated mechanism and reveal that a tyrosine-mediated HAT process is involved.

Divergent Photosensitizer Controlled Reactions of 4-Hydroxycoumarins and Unactivated Olefins: Hydroarylation and Subsequent [2+2] Cycloaddition.

Herein, we report a photoinduced approach for hydroarylation of unactivated olefins using 4-hydroxycoumarins as the arylating reagent. Key to the success of this reaction is the conversion of nucleophilic 4-hydroxycoumarins into electrophilic carbon radicals via photocatalytic arene oxidation, which not only circumvents the polarity-mismatch issue encountered under ionic conditions but also accommodates a broad substrate scope and inhibits side reactions that were previously observed. Moreover, divergent reactivity was achieved by changing the photocatalyst, enabling a subsequent [2+2] cycloaddition to deliver cyclobutane-fused pentacyclic products that are otherwise challenging to access in high yields and with high diastereoselectivity. Mechanistic studies have elucidated the mechanism of the reactions and the origin of the divergent reactivity.

Formal Synthesis of Arboridinine Enabled by a Double-Mannich Reaction.

A formal synthesis of arboridinine has been achieved. In this synthesis, a double-Mannich reaction of the complex multisubstituted cyclohexanone was used to form the core skeleton of arboridinine.

Divergent Synthesis of Skeletally Distinct Arboridinine and Arborisidine.

A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site-selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site-selective intramolecular α-amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.