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)2PYDZ (1) has been shown to follow Michaelis−Menten kinetics, demonstrating fast reversible formation of a complex of olefin, OsO4, and 1 prior to the rate-limiting conversion to the Os(VI) ester intermediate. There is a good correlation between the observed binding constants, Km, and the degree of enantioselectivity 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 Ki values have been determined and correlated with inhibitor structure. The strongest inhibitors are compounds with the ability to coordinate to Os(VIII) of the 1·OsO4 complex while simultaneously binding in the pocket formed by the aromatic subunits of the ligand. Parallelism between Km and Ki values and their relationship with structure indicate 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 dihydroxylation which involves (1) rapid, reversible formation of an olefin-Os(VIII) π-d complex and (2) slow rearrangement to the [3 + 2] cycloaddition transition state which is exemplified in Figure 12. In terms of this mechanism, enantioselective acceleration is the result of two factors: (1) enzyme−substrate-like complexation which brings the reactants 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 step due to relief of eclipsing strain about the OsO4−N bond which lowers the activation enthalpy. Taken together with existing data on the Sharpless enantioselective dihydroxylation, the present results strongly support the [3 + 2] cycloaddition pathway and the U-shaped binding pocket which was advanced earlier.