Finding Lead Catalytic Systems for a Rare Versionof Enantioselective Robinson Annulation: Integration of FluorogenicAssays in Catalyst Screening

摘要

Among the several variants of the highly useful and versatile Robinson annulation, a particular variation that involves ketones reacting with nonenolizable enones, while the α-carbons of the ketones act as nucleophiles at both steps of this cascade process, remains largely unexplored. Moreover, such a catalytic enantioselective reaction is exceptionally rare. While pursuing catalysis of this transformation, we developed two fluorogenic assays that, in combination with other analytic techniques, enabled rapid screening of several sets of catalysts. The first set of polymer-bound aminourea bifunctional organocatalysts was screened using a two-step fluorogenic protocol, designed for slower (e.g., heterogeneous) catalysts. Robinson annulation of acetone with 4′-nitrochalcone formed 3-(4-nitrophenyl)-5-phenyl-2-cyclohexenone, which, after a “developing” reductive treatment, was converted into the corresponding amino derivative, serving as a fluorescent reporter. On the other hand, a range of potentially faster homogeneous catalyst–cocatalyst systems were examined using a direct assay,where 4′-dimethylaminochalcone is converted into the correspondingcyclohexanone fluorescent reporter already upon annulation with acetone.In both cases, the combination of the fluorogenic protocols with high-performanceliquid chromatography-based enantiomeric excess estimation enabledidentification of lead catalysts, which promoted the enantioselectiveversion of this variant of the annulation.