KINETIC INVESTIGATIONS PROVIDE ADDITIONAL EVIDENCE THAT AN ENZYME-LIKE BINDING POCKET IS CRUCIAL FOR HIGH ENANTIOSELECTIVITY IN THE BIS-CINCHONA ALKALOID CATALYZED ASYMMETRIC DIHYDROXYLATION OF OLEFINS

The Sharpless enantioselective dihydroxylation of terminal olefins by OsO4 using the catalytic chiral ligand (DHQD)(2)PYDZ (1) has been show n to follow Michaelis-Menten kinetics, demonstrating fast reversible f ormation of a complex of olefin, OsO4, and 1 prior to the rate-limitin g conversion to the Os(VI) ester intermediate. There is a good correla tion between the observed binding constants, K-m, and the degree of en antioselectivity of the dihydroxylation indicating that van der Waals binding of the substrate by 1 . OsO4 is important to enantioselective rate enhancement. Inhibition of the oxidation by various compounds has been demonstrated kinetically using Dixon analysis of the data, and K -i values have been determined and correlated with inhibitor structure . The strongest inhibitors are compounds with the ability to coordinat e to Os(VIII) of the 1 . OsO4 complex while simultaneously binding in the pocket formed by the aromatic subunits of the ligand. Parallelism between K-m and K-i values and their relationship with structure indic ate similar binding in the substrate and inhibitor complexes with 1 . OsO4. The kinetic, structural, and stereochemical data, as summarized in Tables 1 and 3, support a mechanism for the enantioselective dihydr oxylation which involves (1) rapid, reversible formation of an olefin- Os(VIII) pi-d complex and (2) slow rearrangement to the [3 + 2] cycloa ddition transition state which is exemplified in Figure 12. In terms o f this mechanism, enantioselective acceleration is the result of two f actors: (1) enzyme-substrate-like complexation which brings the reacta nts together in the appropriate geometry for further conversion to the predominating enantiomer, thereby providing a high effective reactant concentration (entropic effect) and (2) a driving force in the next s tep due to relief of eclipsing strain about the OsO4-N bond which lowe rs the activation enthalpy. Taken together with existing data on the S harpless enantioselective dihydroxylation, the present results strongl y support the [3 + 2] cycloaddition pathway and the U-shaped binding p ocket which was advanced earlier.