Enantioselective E/Z-isomerization of axially chiral piperidones by photochemical deracemization

Photochemical E/Z-isomerization reactions are a powerful tool to transform the thermodynamically favored E-alkene into the desired but unfavored Z-alkene. Although, Z-alkenes are a common motif in natural products and biologically active molecules, their selective formation is not trivial. Since then, photochemical E/Z-isomerization is a major research field in modern molecular photochemistry but the E/Z-stereocontrol of carbon-carbon double bonds remained a central challenge in olefin chemistry. Usually, in typical E/Z-photoisomerizations the isomers are distinguished due to their different triplet energy. In our example, the stereoselectivity is controlled by molecular recognition using a chiral triplet sensitizer 1 allowing the selective excitation of one of the isomers over the other. This enables the conversion of a racemic mixture into a single enantiomer with excellent atom economy. The loss of entropy during the reaction is compensated with the energy of light.
The chiral thioxanthone sensitizer 1 is able to efficiently deracemize the axially chiral piperidinones with a low catalyst loading (as low as 2 mol%) in excellent yields and enantiomeric excess. Silicon congeners have shown to be superior in comparison to their carbon analogues, showing higher selectivity in the photochemical reaction. Furthermore, we were able to vary the ring size bearing the chiral center to unlock the deracemization of five-membered ring compounds. The substrate and the catalyst contain a lactam binding motif and association of the substrate to the chiral catalyst are expected to work via a two point hydrogen bonding interaction. The obtained silicon containing chiral products can be easily transformed into their corresponding alcohols with retention of the configuration whereas, subsequent transformations at the double bond gives access to further enantioenriched products. This reaction represents a novel enantioselective E/Z-photoisomerization of an alkene has evolved into a compelling reaction for the synthesis of valuable chiral buildings blocks.

Photochemical deracemization of piperidinones using chiral thioxanthon 1 as sensitizer.