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 and ,
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 . 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.