Asymmetric cyclization of 2′-hydroxychalcones to flavanones: Catalysis by chiral Brønsted acids and bases

The asymmetric cyclization of 2′-hydroxychalcones to flavanones is a basic, enzyme-catalyzed step in the biosynthesis of flavonoid natural products, but poses a long-standing problem for asymmetric catalysis with small molecule catalysts. Earlier claims concerning the realization of an asymmetric flavanone synthesis by means of camphorsulfonic acid as chiral Brønsted acid catalysts were reinvestigated using accurate HPLC methods for quantification of enantiomer ratios. The previous claims of asymmetric induction were thus shown to be untenable. On the other hand, cinchona alkaloids serve as chiral Brønsted base mediators for the asymmetric cyclization of either 6′-substituted 2′-hydroxychalcones or 2′,6′- dihydroxychalcones. 2′,6′-Dihydroxy-4,4′-dimethoxychalcone, for instance, cyclized to give the naturally occurring naringenin-4′,7- dimethyl ether in up to 64 % ee at 81 % conversion. The catalysis shows a marked dependency of the enantiomeric excess of the product on the catalyst, solvent and reactant concentration. Based on these successful examples of asymmetric cyclizations of 2′-hydroxychalcones to flavanones, requirements for more active asymmetric catalysts can be defined.