Acceleration of an Aromatic Claisen Rearrangement via a Designed Spiroligozyme Catalyst that Mimics the Ketosteroid Isomerase Catalytic Dyad

A series
of hydrogen-bonding catalysts have been designed for the
aromatic Claisen rearrangement of a 1,1-dimethylallyl coumarin. These
catalysts were designed as mimics of the two-point hydrogen-bonding
interaction present in ketosteroid isomerase that has been proposed
to stabilize a developing negative charge on the ether oxygen in the
migration of the double bond. Two hydrogen
bond donating groups, a phenol alcohol and a carboxylic acid, were
grafted onto a conformationally restrained spirocyclic scaffold, and
together they enhance the rate of the Claisen rearrangement by a factor
of 58 over the background reaction. Theoretical calculations correctly
predict the most active catalyst and suggest that both preorganization
and favorable interactions with the transition state of the reaction
are responsible for the observed rate enhancement.