Proton Source Guides Two-Way Selectivity

Chemists have found an unusual switch in enantioselectivity––from 92% of one enantiomer to 91% of the other––by changing the proton source in a reaction used to synthesize isoflavanones (Chem. Eur. J. 2014, DOI: 10.1002/chem.201405246). According to the researchers, this is the first example of dual stereocontrol in an asymmetric protonation reaction. The observation could ease the synthesis of customized isoflavanones, which are plant metabolites with immunosuppressive, antibacterial, and anticancer activities. To prepare natural and designed isoflavanones, Pat Guiry and coworkers at University College Dublin used a palladium-catalyzed decarboxylative asymmetric protonation reaction developed earlier by Brian M. Stoltz’s group at Caltech. When Guiry’s team switched the proton source from Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) to formic acid, they were surprised to find that the stereochemistry of the substituted chromanone product switched from 92% (R) to 91% (S). The mechanism of the switch remains unclear. They subsequently observed the same enantiodivergence when preparing α-aryl cyclopentanones and cyclohexanones (J. Org. Chem. 2014, DOI: 10.1021/jo5014806). “I hope others will find use in the reaction and that the stereochemical twist might prove to be more common than not,” Stoltz comments. “The synthetic opportunities are great.”