ChemInform Abstract: QUANTUM‐CHEMICAL SIMULATION OF THE ACID‐, BASE‐ AND ENZYME‐CATALYZED ISOMERIZATION OF Δ5‐3‐KETO STEROIDS

Abstract

?5-3-Keto steroids are isomerized to ?4-3-keto steroids by acid, base and enzyme catalysis. The latter reaction occurs by a suprafacial [1,3] H shift from the 4s to the 6s position. These reactions have been simulated using propene and 3-butenal as substrates. The catalytic effect of a number of bases, B, on the migrating H atom has been studied. The MINDO/3 proton affinities of a group of bases, relative to the affinity of NH3, correlated very well with values calculated using ab initio methods with a large basis set and with experimental gas-phase data. The semi-empirical MINDO/3 method has been used to study catalysis by H2O, NH3, formamidine, imidazole, HCOO- and OH- on the suprafacial [1,3] H shift in propene. Similar trends in barrier heights were found with STO-3G and 4-31G calculations. A linear dependence of activation enthalpy upon the relative proton affinity of the catalysts could be demonstrated. As a more realistic model for the enzymatic isomerization of 3-keto steroids, the 3-butenal ? 2-butenal rearrangement has been studied. Distinct co-operation between proton acceptors, B, and proton donors, AH, interacting with the carbonyl group, could be established. Acid catalysis was simulated using AH = H3O+ and B = H2O, base catalysis in the absence of AH with B = OH- and enzyme catalysis using AH = imid · H+ and B = HCOO-, MINDO/3 calculated activation enthalpies were 28.0, 8.9 and -1.0 kcal · mol-1, respectively. These exhibit the same sequence as the experimental values of 14.0, 11.4 and 5.0 kcal · mol-1, found under the respective conditions. The electron distributions demonstrated that the reactions proceed more readily when the ionogenic component is more pronounced in the transition state. Almost complete deprotonation of the substrate occurs in the base-catalyzed and the enzyme-catalyzed reactions, giving rise to intermediates similar in structure to the dienol anion and the neutral dienol, respectively. When catalyzed, suprafacial shifts were favoured over the antarafacial shifts.