Mechanism of Chorismate Mutase: Contribution of Conformational Restriction to Catalysis in the Claisen Rearrangement

The mechanism of the enzyme- and antibody-catalyzed Claisen rearrangement of chorismate to prephenate was investigated experimentally on model compounds and by using quantum chemistry calculations at the Becke3LYP/6-31G* level of theory. Conformational restriction of the allyl vinyl ether fragment to the reactive chairlike conformation in 1 induces a 2 × 105-fold rate acceleration (ΔΔG⧧ = 7.3 kcal/mol) of the Claisen rearrangement in C6D6 relative to an unrestricted analogue 3. A direct relationship between activation barrier lowering and the distance between reactive termini has been observed in additional model systems. Compression of the reactive centers from 4.0 to 3.0 A results in a barrier lowering from 24 kcal/mol to 12 kcal/mol in one conformationally restricted model. Further compression reduces the activation barrier to a mere 4 kcal/mol. Rearrangement rate increases via conformational restriction and reactive center compression derive mainly from ground-state destabilization in which entropic f...