Taking a cue from human vision, researchers at the Institute of Chemical Research of Catalonia (ICIQ), Tarragona, Spain, have developed a photocatalytic method for enantioselective β-alkylation of enals. Their approach relies on forming chiral iminium ions and then activating them with a light emitting diode (LED).
In the retina of the eye, an iminium ion triggers vision when excited by light, the researchers explain. By chemically modifying natural amino acid proline, the Spanish team designed a set of tailored organocatalysts that react with the substrate of the reaction to yield an intermediate (whose formation is clearly indicated by a color change). Shining a high-power purple LED on the chemicals then activates an enantioselective reaction (Figure 1). The approach can produce either enantiomer, depending upon the starting proline chosen.
“Despite being a well-known mechanism in biochemistry, the photo-excitation of iminium ions hadn’t been used to make chiral molecules yet,” notes Paolo Melchiorre, ICIQ group leader. “Thanks to this novel approach, triggered by visible light, we can obtain products that were impossible to achieve using traditional thermally activated transformations,” he adds.
The organocatalysts avoid the economic and environmental issues posed by palladium, ruthenium and other metallic catalysts, and can promote reactions at ambient temperatures, say the researchers. In laboratory tests, they obtained yields as high as 87% at an enantiomeric excess of up to 88%. Those are about the best results possible in a batch system, admits Melchiorre. Flow chemistry might provide a way to increase productivity and selectivity, and the researchers hope to investigate a continuous system in the near future, he notes.
“…By translating the tools governing the success of enantioselective iminium-ion catalysis into the realm of photochemical reactivity, we can provide novel catalytic frameworks for enantioselective photochemistry, expanding the way chemists think about making chiral molecules,” he stresses.
“We now know… that the photoexcitation of iminium ions is not restricted to organic silanes as substrates, but it can be considerably expanded to develop other photochemical enantioselective reactions. We are now exploring the possibility to apply this strategy for the design of light-triggered radical cascade reactions, which can build stereochemically dense and structurally complex molecules from easily available starting materials in a single step.”
More details on the method appear in a recent article in Nature Chemistry.