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

Article abstract of DOI:10.1021/ja952567z

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

Full text of DOI:10.1021/ja952567z

J. Am. Chem. Soc. 1996, 118, 319-329
319
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
E. J. Corey* and Mark C. Noe
Contribution from the Department of Chemistry, HarVard UniVersity,
Cambridge, Massachusetts 02138
ReceiVed July 31, 1995X
Abstract: 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.
Introduction
substrates such as 2 in a binding pocket composed of the two
parallel methoxyquinoline units, OsO4 and the pyridazine
connector, as shown, (2) staggered geometry about the Os-N
bond of the bis-cinchona-OsO4 complex, (3) the proximity of
one axial oxygen (Oa) and one equatorial oxygen (Oe) of the
complexed OsO4 unit to the olefinic carbons of the bound
substrate, as shown, and (4) a minimum motion pathway from
this arrangement for the [3 + 2] cycloaddition which directly
produces the pentacoordinate osmate ester in the energetically
most favorable geometry. The rate acceleration for the observed
enantioselective pathway relative to other modes is due to the
favorable free energy of activation for the reaction from the
complex 3 in which the reactants are held in a manner which is
ideal for the formation of the thermodynamically more stable
osmate ester. Dihydroxylation of the opposite olefin face to
that shown in 3 is unfavorable due to the fact that there is no
three-dimensional arrangement for simultaneous π-facial ap-
proach of the olefin to the oxygens labeled as Oa and Oe and
favorable interaction with the binding pocket.4 X-ray crystal-
lographic data suggest that the pyridazine ring at the bottom of
the U-shaped cavity tends to be oriented so as to allow
conjugation of the ring and the two alkoxy substituents, with
the N-N side of the ring participating in binding to the substrate,
though the exact tilt of this ring during reaction probably varies
Starting from the initial observation that dihydroquinidine
acetate catalyzes the OsO4-promoted dihydroxylation of olefins
and produces 1,2-diols with modest enantioselectivity, for
example R/S ) ca. 4 for styrene,1 Sharpless and co-workers
screened many other derivatives of dihydroquinidine with
gradual improvement of enantioselectivity.2 The highest enan-
tioselectivities were observed with bis-cinchona alkaloid deriva-
tives of the type shown in formula 1 (R/S ) 32). For some
time, we have been studying the mechanistic basis for enan-
tioselectivity in the OsO4-promoted dihydroxylation of olefins
using bis-cinchona alkaloids such as 1 as catalysts.3 This work
has led to the proposal of a transition-state model which can be
summarized by formula 3 for the specific case of allyl
4-methoxybenzoate (2) as substrate and the pyridazine-linked
bis-dihydroquinidine derivative 1 ((DHQD)2PYDZ). This tran-
sition state and the mechanistic pathway have the following char-
acteristics: (1) a preference for the U-shaped conformation as
in 3 for the OsO4 complex, which has the ability to hold olefinic
X Abstract published in AdVance ACS Abstracts, December 15, 1995.
(1) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 4263.
(2) For a recent review of the development and applications of the
Sharpless asymmetric dihydroxylation, see: Kolb, H. C.; VanNieuwenhze,
M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
(3) (a) Corey, E. J.; Noe, M. C.; Sarshar, S. J. Am. Chem. Soc. 1993,
115, 3828. (b) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115,
12579. (c) Corey, E. J.; Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994,
35, 2861. (d) Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett.
1994, 35, 6427.
(4) (a) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1994, 116, 12109. (b) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am.
Chem. Soc. 1995, 117, 10805. (c) Corey, E. J.; Noe, M. C.; Guzman-
Perez, A. J. Am. Chem. Soc. 1995, 117, 10817.
0002-7863/96/1518-0319$12.00/0 © 1996 American Chemical Society

320 J. Am. Chem. Soc., Vol. 118, No. 2, 1996
Corey and Noe
Figure 1. Three views of the proposed transition-state assembly for the dihydroxylation of 2.
Figure 2. Three views of the proposed transition-state assembly for the dihydroxylation of 4.
slightly with substrate.3c When allyl 4-methoxybenzoate is used
as reactant, excellent binding of this substrate can be expected
because of extensive π-contact of both faces of the allyl and
4-methoxybenzoate moieties with the two methoxyquinoline
units and edge contact with the pyridazine ring.4b,c
substrate which are apparent from Figure 1 suggest the pos-
sibility of a reversibly formed complex of catalyst and substrate
which might precede transition state development in a manner
paralleling reversibly formed enzyme-substrate complexes. It
became apparent from these considerations that kinetic studies
of the dihydroxylation of appropriate substrates might reveal
the existence of such an intermediate by the appearance of
Michaelis-Menten behavior.5
The transition state model described above accommodates
all of the experimental facts of which we are aware. In addition,
it has also been of great predictive value. For instance, the
model predicted the possibility of position and enantioselective
dihydroxylation of retinyl acetate (4) at the 2,3-double bond.
This result was demonstrated experimentally and applied to a
successful and simple synthesis of the signaling retinoid (14R)-
14-hydroxy-4,14-retro-retinol via transition state 5; see also
Figure 2.6
(5) Detailed kinetic studies of the stoichiometric reactions of various
cinchona alkaloid-OsO4 catalysts with several olefins have been carried out
by Sharpless and co-workers. See: (a) Andersson, P. G.; Sharpless, K. B.
J. Am. Chem. Soc. 1993, 115, 7047. (b) Kolb, H. C.; Andersson, P. G.;
Bennani, Y. L.; Crispino, G. A.; Jeong, K.-S.; Kwong, H.-L.; Sharpless,
K. B. J. Am. Chem. Soc. 1993, 115, 12226. (c) Kolb, H. C.; Andersson, P.
G.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116, 1278.
Three views of transition state 3 using a space-filling
representation are shown in Figure 1. The complementary
shapes and the potential for binding between the catalyst and
(6) Corey, E. J.; Noe, M. C.; Guzman-Perez, A. Tetrahedron Lett. 1995,
36, 4171.

Bis-Cinchona Alkaloid Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 118, No. 2, 1996 321
Results and Discussion
The first positive indication that Michaelis-Menten kinetic
behavior might be exhibited in the bis-cinchona alkaloid
catalyzed dihydroxylation of olefins was obtained from a set
of competition experiments involving allyl 4-methoxybenzoate
(2) and allyl triisopropylsilyl ether (6). These substrates were
selected for initial studies due to the large differences in their
reactivity with the (DHQD)2PYDZ‚OsO4 catalyst (1‚OsO4) that
were anticipated from application of the transition state model
depicted in Figure 1. Stabilizing aryl-aryl interactions between
the allylic 4-methoxybenzoate group of 2 within the U-shaped
binding pocket of the (DHQD)2PYDZ‚OsO4 catalyst (1‚OsO4)
should accelerate the overall reaction rate of this substrate
relative to that of 6 which cannot effectively bind to the catalyst
due to the large steric demand of the allylic triisopropylsilyloxy
group. The catalytic asymmetric dihydroxylation of a 1:1
mixture of these substrates was followed by gas chromatographic
analysis using tetralin as an internal standard. The conversion
of each substrate as a function of total reaction time is indicated
in Figure 3. As shown, the (DHQD)2PYDZ‚OsO4 catalyst
(1‚OsO4) selectively dihydroxylates allyl 4-methoxybenzoate (2)
before beginning to react with allyl triisopropylsilyl ether (6).
Only trace amounts of 6 react during the first 80% of the reaction
of 2, and the calculated ratio of the dihydroxylation rates for
these substrates during this period is >50:1. Allyl triisopro-
pylsilyl ether (6) begins to react at a more rapid rate only after
most of the allyl 4-methoxybenzoate 2 is consumed. The
absence of an induction period in the independent reaction of
allyl triisopropylsilyl ether (6) was verified by a control
experiment in the absence of substrate 2. In this case, the
intrinsic rate of reaction of 2 was approximately six-fold faster
than that of 6.7
The observation of inhibition of the dihydroxylation of allyl
triisopropylsilyl ether (6) in the presence of allyl 4-methoxy-
benzoate (2) is readily explained in terms of a substrate-catalyst
binding equilibrium that exists prior to transition state develop-
ment in the asymmetric dihydroxylation. According to this
model, both substrates 2 and 6 compete for a single active
binding site on the bis-cinchona alkaloid catalyst 1‚OsO4.
Substrate 2 binds more tightly (lower Km) due to the favorable
aryl-aryl stacking and other van der Waals interactions with
the catalyst relative to substrate 6, which cannot fit well into
the catalyst binding cleft due to unfavorable steric repulsions
involving the bulky triisopropylsilyloxy group. In the presence
of a low, substoichiometric amount of 1 (ca. 1 mol % based on
total olefin), nearly all of the catalyst will be associated with 2
Figure 3. Reaction profile for the competitive catalytic asymmetric
dihydroxylation of allyl 4-methoxybenzoate (2) (0.08 M) and allyl
triisopropylsilyl ether (6) (0.08 M) using the (DHQD)2PYDZ ligand 1
(1.6 mM) and K2OsO4‚2H2O (0.4 mM) in 1:1 tert-butyl alcohol-H2O
at 0 °C.
during the initial stages of the reaction, and the reaction of 6
will be suppressed. As 2 is consumed, the amount of free
catalyst 1‚OsO4 increases, and the oxidation of 6 proceeds at a
more rapid rate. Such kinetic behavior has been observed for
several enzymatic reactions, and a theoretical treatment has been
derived.8
Similar reactivity was observed in the competitive asymmetric
dihydroxylation of 4-vinylanisole (8) vs 1-decene (10) and
4-vinylanisole (8) vs allyl triisopropylsilyl ether (6). In each
case, the substrate that exhibits higher enantioselectivity in the
corresponding independent dihydroxylation reaction is also that
which suppresses the dihydroxylation of the other olefin.
Moreover, the degree of suppression reflects the difference in
enantioselectivities in the dihydroxylation reaction and in
binding affinities of the two substrates to the catalyst 1‚OsO4
(Vide infra). Thus, vinylanisole partially suppresses the dihy-
droxylation of 1-decene and allyl triisopropylsilyl ether but has
little effect on the dihydroxylation of styrene using the
(DHQD)2PYDZ‚OsO4 catalyst, 1‚OsO4, as shown in Figures
4-6, respectively.
More detailed studies were undertaken in order to further
examine the relationships between catalyst and substrate struc-
ture, binding, and enantioselectivity in the catalytic asymmetric
dihydroxylation reaction using Michaelis-Menten analysis.
Such a study of the catalytic reaction requires that the following
conditions hold: (1) catalyst and substrate react reversibly to
form a complex; (2) the equilibrium association and dissociation
rates for the catalyst-substrate complex are rapid relative to
the rate of formation of the osmate ester intermediate; (3) the
catalyst concentration is small, such that formation of the
catalyst-substrate complex does not alter the total substrate
concentration; (4) the overall reaction rate is limited by the
conversion of the catalyst-substrate complex to the osmate ester
intermediate and not by subsequent steps of the catalytic cycle;
and (5) the velocity is measured during the initial stages of the
(8) For examples of this phenomenon in biological systems, see: (a)
Hackette, S. L.; Skye, G. E.; Burton, C.; Segel, I. H. J. Biol. Chem. 1970,
245, 4241. (b) Dixon, M.; Webb, E. C. Enzymes, 2nd ed.; Chapter 4, p 88.
For another example observed by Willstatter, R.; Kuhn, R.; Lind, O.;
Memmen, F. Z. Physiol. Chem. 1927, 167, 303. For theoretical treatments
of kinetic behavior observed in cases of mutual competitive inhibition,
see: (c) Pocklington, T.; Jeffery, J. Biochem. J. 1969, 112, 331. (d) Dixon,
M.; Webb, E. C. Enzymes, 2nd ed.; Chapter 4, pp 84-87.
(7) Rates of reaction refer to initial velocities during the first 5-20% of
the reaction of any given substrate. Concentrations refer to the organic
layer (ca. 2:1 t-BuOH‚H2O) and were shown by GC and UV analysis to be
within 5% of the calculated values.

322 J. Am. Chem. Soc., Vol. 118, No. 2, 1996
Corey and Noe
Figure 6. Reaction profile for the competitive catalytic asymmetric
dihydroxylation of styrene (0.04 M) and 4-vinylanisole (0.04 M) using
(DHQD)2PYDZ ligand 1 (1.0 mM) and K2OsO4‚2H2O (0.5 mM) in
1:1 tert-butyl alcohol-H2O at 0 °C.
Figure 4. Reaction profile for the competitive catalytic asymmetric
dihydroxylation of decene (0.08 M) and 4-vinyl anisole (0.08 M) using
(DHQD)2PYDZ ligand 1 (1.6 mM) and K2OsO4‚2H2O (0.4 mM) in
1:1 tert-butyl alcohol-H2O at 0 °C.
ordinate osmate ester. This species is subsequently hydrolyzed
to produce the diol and OsO2(OH)42-. This Os(VI) species then
migrates to the aqueous layer, where it is reoxidized by the
stoichiometric oxidant K3Fe(CN)6 to regenerate OsO4.11c In
cases where the olefin is di-, tri-, or tetrasubstituted, the rate
limiting step is the hydrolysis of the osmate ester. However,
for most terminal or 1,1-disubstituted substrates, the hydrolysis
of the intermediate osmate ester is rapid, and initial attack of
the olefin by osmium tetroxide has been found to be rate
limiting.12 The studies reported herein were carried out
exclusively with monosubstituted or deactivated 1,2-disubsti-
tuted olefins for which addition to the olefin is anticipated to
be rate limiting. For the case of styrene careful control studies
were carried out which demonstrated that under the conditions
of the kinetic studies described herein both the oxidation step,
Os(VI) f Os(VIII), and the hydrolysis of cyclic osmate ester
to diol are relatively fast compared to the conversion of styrene
to the cyclic osmate ester, which therefore is the rate-limiting
step. First of all, the rate of oxidation of K2OsO2(OH)4 to
Os(VIII) was measured by the stopped-flow method (0.005
M potassium (VI) osmate, 0.08 M K3Fe(CN)6, and 0.08 M
K2CO3 in H2O at 25 °C) and was found to be very fast with the
Figure 5. Reaction profile for the competitive catalytic asymmetric
dihydroxylation of allyl triisopropylsilyl ether (0.08 M) and 4-vinyl-
anisole (0.08 M) using (DHQD)2PYDZ ligand 1 (1.6 mM) and
K2OsO4‚2H2O (0.4 mM) in 1:1 tert-butyl alcohol-H2O at 0 °C.
reaction.9 Assumptions (1) and (2) are clearly valid since
the catalyst possesses one binding site for the substrate, and
since association and dissociation of the substrate with the
U-shaped binding pocket should be very rapid compared to
cycloaddition to form the osmate ester. Assumptions (3) and
(5) can be assured by an appropriate experimental design.
Assumption (4) is valid only if the steps to regenerate the
catalyst from the osmate ester intermediate are rapid relative to
its formation.10
pseudo-first-order rate constant, k1, determined to be >100 s-1
.
This is a much faster reaction than the catalyzed formation of
osmate ester from styrene for which k1 has been measured by
(10) For the case where this assumption is invalid, an equation similar
to the Henri-Michaelis-Menten equation can be derived using the Briggs-
Haldane steady state approach. Thus, V ) Vmax[olefin]/(Km + [olefin])
where Vmax ) k2k3[catalyst]0/(k2 + k3) and Km ) [k3(k-1 + k2)]/[(k2 + k3)‚
k1]. For these equations, the scheme at the end of the reference applies.
Thus, when the complexation-decomplexation equilibrium is fast, k1 and
k-1 . k2. If k2 is rate limiting, then k3 . k2 and Vmax ) k2[catalyst]o and
Km ) k-1/k1, as anticipated for normal Michaelis-Menten behavior. When
k3 is rate limiting, k3 , k2, and the same qualitative kinetic behavior is
observed, but Vmax ) k3[catalyst]o and Km ) (k-1/k1)(k3/k2), so the Vmax
reflects the maximum hydrolysis rate, and the Km reflects the initial catalyst-
substrate equilibrium constant multiplied by a factor of k3/k2. See: Roberts,
D. V. Enzyme Kinetics; Cambridge University Press: London, 1977; pp
35-42.
The sequence of events in the catalytic asymmetric dihy-
droxylation reaction using the K3Fe(CN)6 secondary oxidant
system has previously been demonstrated.11 The reaction
mixture is triphasic, consisting of a solid phase of undissolved
salts, a salt-containing aqueous phase, and an organic phase
consisting of the ligand, substrate, and catalyst-bound osmium
tetroxide in ca. 2:1 tert-butyl alcohol-water (ratio determined
k2
98
catalyst + olefin {kk } [catalyst‚olefin]
1
-1
k3
1
by us using both H NMR and density measurements on the
osmate ester
98 catalyst + diol
vacuum-transferred liquid). The first irreversible step in the
catalytic sequence is oxidation of the olefin by the bis-cinchona
alkaloid ligand osmium tetroxide complex to form a pentaco-
(11) (a) Minato, M.; Yamamoto, K.; Tsuji, T. J. Org. Chem. 1990, 55,
766. (b) Kwong, H.-L.; Sorato, C.; Ogino, Y.; Chen, H.; Sharpless, K. B.
Tetrahedron Lett. 1990, 31, 2999. (c) Ogino, Y.; Chen, H.; Kwong, H.-L.;
Sharpless, K. B. Tetrahedron Lett. 1991, 32, 3965.
(12) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059.
(9) Segel, I. H. Enzyme Kinetics - BehaVior and Analysis of Rapid
Equilibrium and Steady-State Enzyme Systems; John Wiley & Sons, Inc.:
New York, 1993; pp 18-22.

Bis-Cinchona Alkaloid Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 118, No. 2, 1996 323
Table 1. Comparison of the Michaelis-Menten parameters Km
and Vmax and Observed Enantioselectivity in the Catalytic
Asymmetric Dihydroxylation of Olefinsa
Figure 7. Plot of initial velocity versus initial olefin concentration
showing saturation behavior for the (DHQD)2PYDZ‚OsO4 catalyzed
asymmetric dihydroxylation using 1 mM (DHQD)2PYDZ ligand, 0.5
mM K2OsO4‚2H2O in 1:1 tert-butyl alcohol-water at 0 °C.
a Unless otherwise indicated, all reactions were performed at 0 °C
in 1:1 tert-butyl alcohol-water using the (DHQD)2PYDZ ligand (1
mM) and K2OsO4‚2H2O (0.5 mM).
since at these concentrations significant amounts of free OsO4
and ligand are present in equilibrium with OsO4‚ligand.5c Thus,
the values of Vmax given in Table 1, refer specifically to 1 mM
ligand and 0.5 mM OsO4. However, the Km values shown in
Table 1 are independent of the exact concentrations of ligand
and OsO4 within the catalytic range. That follows since Km is
equal simply to the substrate concentration at the point where
free catalyst and substrate-catalyst concentrations are equal.
Figure 8. Lineweaver-Burk plot for the catalytic asymmetric dihy-
droxylation of styrene under the conditions noted in Figure 7.
Sharpless et al.5c (as confirmed by us) to be ca. 1 s-1. We
have also measured the pseudo-first-order rate constant for
hydrolysis of the cyclic osmate ester of styrene under our kinetic
conditions (in 0.025 M K2CO3 in 2:1 tert-butyl alcohol-H2O
at 0 °C) and found k1 to be >200 s-1, i.e., very fast compared
to formation of cyclic osmate ester. Similarly, control experi-
ments showed that for the case of methyl cinnamate as substrate,
the formation of osmate ester is the rate-limiting step in the
catalytic dihydroxylation under the kinetic conditions described
herein.
The strong correlation between the binding cosntants Km and
the enantioselectivities observed in the catalytic asymmetric
dihydroxylation imply that binding interactions between the
catalyst and the substrate are crucial for enantioselection in the
dihydroxylation. The structural factors important for binding
of the substrate to the catalyst are consistent with those observed
earlier for high enantioselectivity in the reaction.3 Olefins that
possess hydrophobic substituents of <4 Å thickness, particularly
aromatic groups, exhibit the strongest binding affinities and
highest enantioselectivities in the reaction, while those substrates
which possess bulky groups, such as allyl triisopropylsilyl ether
6, exhibit weak binding and poor levels of enantioselectivity.
These observations suggest that the catalyst imposes steric
constraints on the substrates on which it operates that are similar
to the substrate requirements of enzymes for activity.3b The
lower enantioselectivities observed with substrates 6 and 10 can
be understood in terms of competing non-face selective reaction
with 1‚OsO4 without simultaneous binding to the U-shaped
pocket, i.e., to other O-Os-O sites. Moreover, alteration of
the catalyst binding pocket affects both its ability to bind
substrates and the enantioselectivity of the dihydroxylation.
Thus, the truncated DHQD-PYDZ-OMe ligand 13 and OsO4
effect the dihydroxylation of styrene at a slower rate and with
much lower enantioselectivity than is observed for the corre-
Initial velocities for the reaction of various olefins in the
catalytic asymmetric dihydroxylation were measured in order
to determine binding constants for these substrates. Reactions
were followed by gas chromatographic analysis using an internal
standard and were carried out to 10-30% conversion. The
(DHQD)2PYDZ‚OsO4 catalyst displays saturation behavior with
respect to olefin concentration, as shown in Figure 7 for the
case of styrene. Binding constants for the various olefins were
obtained from Lineweaver-Burk plots of 1/velocity vs 1/[sub-
strate]. A representative plot for the case of styrene is shown
in Figure 8. A comparison of Km, Vmax, and enantioselectivity
values for the olefins tested appears in Table 1. These data
were obtained for a fixed concentration of ligand (1 mM) and
of OsO4 (0.5 mM); increasing the concentration of OsO4 (or
ligand) would increase the rate of reaction and, hence, Vmax
,

324 J. Am. Chem. Soc., Vol. 118, No. 2, 1996
Corey and Noe
Table 2. Observed and Calculated Initial Velocity Ratios (Φ) for
Table 3. Inhibition of the Catalytic Asymmetric Dihydroxylation
of Styrene Using the (DHQD)2PYDZ‚OsO4 Catalyst 1‚OsO4
Multiple Substrate Competition Experimentsa
substrate combination
calcd Φ
obsd Φ
styrene-decene
12.3
5.5
5.0
8.6
5.6
4.2
3.4
decene-allyl TiPS ether
4-vinylanisole-styrene
4-vinylanisole-4-CN styrene
3.4
a All reactions were run with 0.04 M initial substrate concentration
using 1 mM (DHQD)2PYDZ ligand and 0.5 mM K2OsO4‚2H2O at 0
°C in 1:1 tert-butyl alcohol-water. The faster reacting olefin is
indicated first.
sponding reaction of ligand 1 and OsO4,3a a consequence of
the much diminished binding capacity of 13‚OsO4 with sty-
rene.13
In order to confirm the validity of the observed catalytic
parameters Km and Vmax, ratios of initial velocities for a few
representative substrates were independently determined by
competition studies and compared with the values from Michae-
lis-Menten analysis.14 As indicated in Table 2, the observed
ratio of rates, Φ, agrees with the corresponding ratio calculated
from the above Michaelis-Menten parameters for each olefin
combination tested.
Since the ratio of initial velocities for the dihydroxylation of
two competing substrates is dictated by the corresponding ratio
of rates for the first irreversible step in the catalytic dihydroxy-
lation, the good agreement between the observed and calculated
ratios Φ provides further support that, for the cases tested above,
the rate limiting step in the catalytic sequence is the initial
oxidation of the substrate double bond and not the subsequent
breakdown of the corresponding osmate ester and also confirms
Figure 9. Dixon plot for the inhibition of the asymmetric dihydroxy-
lation of styrene using the (DQHD)2PYDZ‚OsO4 catalyst by 19. The
initial styrene concentration was 17.5 mM. The reaction conditions
are the same as those detailed in Figure 7.
the reliability of the observed values of Km and Vmax
.
Additional evidence for a catalyst-substrate complex inter-
mediate was also obtained from competitive inhibition studies
involving rationally designed olefinic and non-olefinic inhibitors.
The catalytic asymmetric dihydroxylation of styrene by the
(DHQD)2PYDZ‚OsO4 complex was studied in the presence of
several inhibitors with the results shown in Table 3. In each
case, the inhibition constant Ki was determined from a linear
Dixon plot of 1/v vs inhibitor concentration, [inhibitor], at an
initial substrate concentration of Km. Two representative exam-
ples are shown in Figures 9 and 10. The observation of linear
competitive inhibition indicates that the substrate and the inhibi-
tor compete for association with the same catalyst binding site.
(13) While the ratio of Vmax for the corresponding catalysts 1‚OsO4 and
13‚OsO4 is only 3:1, the ratio of rates for the catalytic dihydroxylation of
styrene involving an equimolar mixture of 1 and 13 will vary between 8:1
and 30:1 at [styrene]o ) 80 mM depending on the extent of conversion
according to the formula
Figure 10. Dixon plot for the inhibition of the asymmetric dihydroxy-
lation of styrene using the (DQHD)2PYDZ‚OsO4 catalyst by 18. The
initial styrene concentration was 17.5 mM. The reaction conditions
are the same as those detailed in Figure 7.
V1
V2
Vmax1 (Km2 + [olefin])
)
Vmax2 (Km1 + [olefin])
(14) The theoretical value for the ratio of initial rates in the competitive
reaction of two substrates at equimolar initial concentrations with a single
enzyme is given by Φ (see equation at end of reference) and VA ) Vmax for
In each case, the strongest inhibition of catalytic activity was
observed for structures possessing two binding groups:
a
substrate A, VB ) Vmax for substrate B, KA ) Km for substrate A and KB
Km for substrate B
)
hydrophobic aromatic group which binds in the catalyst U-
shaped binding pocket and a hydroxyl or amine function which
can coordinate with osmium (VIII). Thus, N-methylnaphtha-
VAKB
Φ )
VBKA

Bis-Cinchona Alkaloid Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 118, No. 2, 1996 325
Figure 11. Three views of the proposed geometry for the complex between 19, OsO4, and (DHQD)2PYDZ ligand (1). The catalyst geometry was
based on the X-ray crystal structure of 1‚CH3I with the following modifications: (a) the methyl group of the methiodide salt was replaced by OsO4
with the eclipsed arrangement about the N-Os bond and the bond distances demonstrated from X-ray studies and (b) the H(8)-C(8)-C(9)-H(9)
dihedral angle was adjusted to ca. 90°.
Figure 12. Stereoformula representation of the complex between allyl 4-methoxybenzoate (2) and the (DHQD)2PYDZ‚OsO4 catalyst (1‚OsO4).
The [3 + 2] cycloaddition reaction to produce the pentacoordinate osmate ester proceeds via rotation of the Os-N bond to the staggered Q‚OsO4
conformation with concurrent oxidation of the substrate double bond.
lene-2-methylamine (14) and 6-methoxynaphthalene-2-methanol
(15) are considerably better inhibitors of catalyst activity than
the corresponding methoxymethyl ether 16. Moreover, inhibi-
tory activity is sensitive to the length of the aromatic substituent
of the inhibitor, as indicated by the better binding constants of
the methoxynaphthylfurfurylamine 19 and alcohol 18 as com-
pared to those of the corresponding naphthalene derivatives 14
and 15.15 A comparison of the binding affinity of 19 with
adamantylmethyl-N-methylamine (20) indicates 90-fold better
binding activity for the former, as expected since the adamantyl
group is too bulky to be accommodated in the binding pocket.
Moreover, the presence of unsaturated functionality also
enhances inhibitory activity. Thus, methyl 6-methoxynaphthyl-
2-propenoate 17 exhibits inhibitory activity that is comparable
to the best non-olefinic inhibitors.16 The dependence of effective
inhibitory activity on the presence of both an extended aromatic
group and an additional coordinating ligand suggests that two
contact sites may be important for binding of these inhibitors.
Indeed, each of the effective inhibitors shown in Table 3
possesses a hydroxyl, amine, or olefinic function which is
capable of association with the Os(VIII) center of the cata-
lyst as the aromatic group is bound within the U-shaped
pocket, as can be seen by the examination of molecular
models. Such two-site binding is illustrated for the case of 19
in Figure 11.
The observation of two-site binding interactions in the
inhibition studies suggests that the asymmetric dihydroxylation
reaction itself involves rapid reversible formation of such a
catalyst-substrate complex prior to transition state development.
This complex would involve contacts between the olefinic
π-orbital and the low-lying d-orbitals of Os(VIII) in addition
to the hydrophobic or aryl-aryl interactions between an olefin
substituent and the catalytic binding pocket that are crucial to
high enantioselection in the asymmetric dihydroxylation. The
proposed geometry of such a complex is indicated in Figure 12
for the asymmetric dihydroxylation of allyl 4-methoxybenzoate
2. Thus, in the case of the bis-cinchona alkaloid catalyzed
asymmetric dihydroxylation, complexation of the olefin with
osmium tetroxide occurs simultaneously with binding of an
olefinic substituent in the U-shaped binding pocket of the
catalyst. Optimum olefin-Os(VIII) d-π contact is attained when
the equatorial oxygen atoms of the complexed OsO4 are eclipsed
with the C-N bonds of the quinuclidine ring. Subsequent
rotation of the OsO4 unit about the Os-N bond relieves these
eclipsing interactions and positions one axial and one equatorial
oxygen proximal to the double bond as required for the five-
membered [3 + 2] cycloaddition transition state and enanti-
oselective production of the Os(VI) ester. This two-site binding
interaction and enantioselective delivery of two oxygen atoms
to the double bond of the substrate are shown in Figure 12.
The enantioselective acceleration (selective acceleration of the
pathway leading to the preferred enantiomer) of the dihydroxy-
lation would then result from a combination of two factors: (1)
favorable complexation which brings the two reactants together
in the appropriate geometry, thereby providing a high effective
concentration (entropic effect) and (2) a driving force due to
(15) Methoxy groups were incorporated into the design of aromatic
inhibitors due to the enhanced solubility of these derivatives relative to the
corresponding nonfunctionalized naphthalenes in the tert-butyl alcohol-
water solvent system used for the dihydroxylation reaction.
(16) Inhibitors 17 and 18 were found to be partially oxidized by the
(DHQD)2PYDZ‚OsO4 catalyst (ca. 5-10% conversion) during the inhibitor
assays.

326 J. Am. Chem. Soc., Vol. 118, No. 2, 1996
Corey and Noe
mL volumetric flask with K2OsO4 (4.6 mg, 0.013 mmol), K3Fe(CN)6
(2.47 g, 7.50 mmol), K2CO3 (1.04 g, 7.52 mmol) and diluting to the
mark with deionized water. A stock solution of (DHQD)2PYDZ ligand
1 was prepared by charging a 10 mL volumetric flask with 1 (7.3 mg,
0.01 mmol) and diluting to the mark with tert-butyl alcohol. A 10 mL
round-bottom flask was charged with 1.00 mL of each of these stock
solutions and was cooled to 0 °C with vigorous magnetic stirring. Since
this mixture consisted of a solid phase of undissolved salts, a salt-
containing aqueous phase, and an organic phase, all substrate and
catalyst concentrations are based on the estimated volume of the organic
phase as 50% of the total reaction volume or 1.0 mL. Thus, the above
mixture is calculated to contain 1 mM (DHQD)2PYDZ ligand 1 and
0.5 mM K2OsO4‚2H2O. A crystal of hydroquinone was added to
solutions of the substituted styrenes to inhibit polymerization of the
olefin. The appropriate amount of olefin solution (see below) was
added, and aliquots were taken at recorded times according to the
following procedure. Approximately 0.02 mL of the reaction mixture
was withdrawn with a Pasteur pipette and was immediately introduced
into a 0.5 mL test tube containing approximately 0.1 mL of saturated
aqueous Na2SO3 solution and 0.2 mL of ethyl acetate. The resulting
mixture was thoroughly agitated, and 0.003 mL of the organic layer
was withdrawn and analyzed by gas chromatography. Reaction rates
were followed by monitoring olefin concentration relative to that of
an internal standard. For each aliquot, the ratio of integrated areas
under the olefin and internal standard peaks were compared with that
measured before the reaction and were scaled against the initial
concentration of olefin. The initial ratio of peak areas for the single
substrate and inhibitor studies was obtained by extrapolation of the
linear plot of the ratio of areas versus total reaction time. In general,
the calculated values agreed to within 5% of those measured from the
initial olefin stock solutions.
Competitive Rate Experiments with Two Substrates. (a) Allyl
4-methoxybenzoate 2 vs allyl triisopropylsilyl ether 6: A stock oxidant
solution was prepared by charging a 25 mL volumetric flask with K2-
OsO4 (3.7 mg, 0.010 mmol), K3Fe(CN)6 (3.95 g, 12.0 mmol), K2CO3
(1.65 g, 12.0 mmol) and diluting to the mark with deionized water. A
stock solution of (DHQD)2PYDZ ligand 1 was prepared by charging a
10 mL volumetric flask with 1 (11.7 mg, 0.0161 mmol) and diluting
to the mark with tert-butyl alcohol. A 10 mL round-bottom flask was
charged with 1.00 mL of each of these stock solutions and was cooled
to 0 °C with vigorous magnetic stirring. A mixture of 2 (0.042 mL,
46 mg, 0.24 mmol), 6 (0.061 mL, 52 mg, 0.24 mmol), and 0.05 mL of
tetralin (added as an internal standard) was prepared, and 0.051 mL of
this solution was added to the reaction mixture prepared above.
Aliquots were taken and analyzed as indicated in the general proce-
dure: GC conditions, injector temperature, 225 °C; detector temperature,
300 °C, FID detection, 120 °C isothermal oven, 1.1 mL/min carrier
gas flow rate; retention times, 2 ) 8.95 min; 6 ) 2.84 min; tetralin )
2.11 min.
the subsequent Os-N bond rotation (from eclipsed to the more
stable staggered geometry) which lowers the activation enthalpy.
Dihydroxylation of the opposite olefin face is disfavored due
to the fact that there is no suitable three-dimensional arrange-
ment for simultaneous interaction of the substrate with osmium
tetroxide and the catalyst binding pocket.
Conclusions
Kinetic studies on the OsO4-promoted dihydroxylation of
olefins using (DHQD)2PYDZ (1) as catalyst have demonstrated
Michaelis-Menten behavior and the intermediacy of a rapidly
and reversibly formed complex of 1‚OsO4‚olefin prior to
transition state development. There is a good correlation
between stability of the initial complex (low Km value) and the
enantioselectivity of the dihydroxylation process. There is also
a good correlation between the ability of various molecules to
inhibit this oxidation and their structural capacity to coordinate
to Os(VIII) while simultaneously fitting into the U-shaped
binding pocket of the catalytic ligand. These results are fully
consistent with a two-step oxidation mechanism involving (1)
reversible formation of an olefin-Os(VIII) π-d complex and
(2) slow rearrangement to the [3 + 2] cycloaddition transition
state, as shown in Figure 12. The [3 + 2] cycloaddition
transition state shown in figure 12, which has previously been
discussed,3b-d,4 adequately explains all of the available experi-
mental evidence, to the best of our knowledge.
A different mechanism involving [2 + 2] addition of the
olefinic bond to complexed OsO4 with interactions between the
substrate and an L-shaped binding area has recently been
proposed by Sharpless.17 A critical analysis of the [2 + 2]
mechanism based on the results presented here and other data
will appear in a forthcoming paper.
Experimental Section
General Methods. All moisture and air sensitive reactions were
performed in oven or flame dried glassware equipped with rubber septa
under a positive pressure of nitrogen or argon. When necessary,
solvents and reagents were distilled prior to use and were transferred
using a syringe or cannula. Reaction mixtures were magnetically
stirred. Thin layer chromatography was performed on Merck precoated
silica gel F-254 plates (0.25 mm). Concentration in Vacuo was
generally performed using a Bu¨chi rotary evaporator. Flash column
chromatography was performed on Baker 230-400 mesh silica gel.
Melting points were determined using a Bu¨chi oil immersion apparatus
and are reported uncorrected for all crystalline products. All other
products were isolated as clear oils. Optical rotations were determined
using a Perkin-Elmer 241 polarimeter. Infrared spectra were recorded
on a Nicolet 5ZDX FT-IR. Nuclear magnetic resonance spectra were
measured with Bruker AM500, AM400, AM300, and AM250 instru-
ments. Proton NMR spectra were obtained with CDCl3 as solvent using
the CHCl3 signal as an internal standard (7.26 ppm). Carbon NMR
spectra were recorded in ppm relative to the solvent signal: CDCl3
(77.07 ppm). Mass spectra and high resolution mass spectra (HRMS)
were recorded on JEOL Model AX-505 or SX-102 spectrometers and
are reported in units of mass to charge (m/e). Chiralcel and Chiralpak
HPLC columns were obtained from Daicel Chemical Industries, Ltd.
Gas chromatographic analysis was performed using a Hewlett Packard
5890A gas chromatograph interfaced to a Hewlett Packard 3392A
integrator. Separations were performed using a Sigma-Aldrich SA-1
capillary column (0.32 mm i.d. × 30 m) under the conditions indicated
below.
(b) 4-Vinylanisole 8 vs Decene 10. A stock oxidant solution was
prepared by charging a 25 mL volumetric flask with K2OsO4 (3.7 mg,
0.010 mmol), K3Fe(CN)6 (3.95 g, 12.0 mmol), K2CO3 (1.65 g, 12.0
mmol) and diluting to the mark with deionized water. A stock solution
of (DHQD)2PYDZ ligand 1 was prepared by charging a 10 mL
volumetric flask with 1 (11.7 mg, 0.016 mmol) and diluting to the mark
with tert-butyl alcohol. A 10 mL round-bottom flask was charged with
1.00 mL of each of these stock solutions and was cooled to 0 °C with
vigorous magnetic stirring. A mixture of 8 (0.032 mL, 32 mg, 0.24
mmol), 10 (0.045 mL, 34 mg, 0.24 mmol), and 0.03 mL of tetralin
(added as an internal standard) was prepared, and 0.036 mL of this
solution was added to the reaction mixture prepared above. Aliquots
were taken and analyzed as indicated in the general procedure: GC
conditions, injector temperature, 250 °C; detector temperature, 300 °C
FID detection, 95 °C isothermal oven, 1.1 mL/min carrier gas flow
rate; retention times, 8 ) 3.12 min; 10 ) 1.73 min; tetralin ) 3.35
min.
General Conditions for Kinetic Experiments. Unless otherwise
indicated, the following general procedure was used for the kinetic
experiments. A stock oxidant solution was prepared by charging a 25
(c) Allyl Triisopropylsilyl Ether 6 vs 4-Vinylanisole 8. A stock
oxidant solution was prepared by charging a 25 mL volumetric flask
with K2OsO4 (3.7 mg, 0.010 mmol), K3Fe(CN)6 (3.95 g, 12.0 mmol),
K2CO3 (1.65 g, 12.0 mmol) and diluting to the mark with deionized
water. A stock solution of (DHQD)2PYDZ ligand 1 was prepared by
charging a 10 mL volumetric flask with 1 (11.7 mg, 0.016 mmol) and
(17) (a) Norrby, P.-O.; Kolb, H. C.; Sharpless, K. B. Organometallics
1994, 13, 344. (b) Norrby, P.-O.; Kolb, H. C.; Sharpless, K. B. J. Am.
Chem. Soc. 1994, 116, 8470. (c) Becker, H.; Ho, P. T.; Kolb, H. C.; Loren,
S.; Norrby, P.-O.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 7315.

Bis-Cinchona Alkaloid Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 118, No. 2, 1996 327
diluting to the mark with tert-butyl alcohol. A 10 mL round-bottom
flask was charged with 1.00 mL of each of these stock solutions and
was cooled to 0 °C with vigorous magnetic stirring. A mixture of 6
(0.061 mL, 52 mg, 0.24 mmol), 8 (0.032 mL, 32 mg, 0.24 mmol), and
0.03 mL of tetralin (added as an internal standard) was prepared, and
0.041 mL of this solution was added to the reaction mixture prepared
above. Aliquots were taken and analyzed as indicated in the general
procedure: GC conditions, injector temperature, 250 °C; detector
temperature, 300 °C, FID detection, 115 °C isothermal oven, 1.1 mL/
min carrier gas flow rate; retention times, 6 ) 2.69 min; 8 ) 1.80
min; tetralin ) 1.92 min.
(d) Styrene (7) vs 4-Vinylanisole (8). The asymmetric dihydroxy-
lation reaction mixture was set up as described in the general procedure.
A mixture of 7 (0.086 mL, 78 mg, 0.75 mmol), 8 (0.100 mL, 101 mg,
0.75 mmol), and 0.08 mL of tetralin (added as an internal standard) in
a 1 mL volumetric flask was diluted to the mark with tert-butyl alcohol,
and 0.053 mL of this solution was added to the reaction mixture
prepared above. Aliquots were taken and analyzed as indicated in the
general procedure: GC conditions, injector temperature, 250 °C,
detector temperature, 300 °C, FID detection, 95 °C isothermal oven,
1.1 mL/min carrier gas flow rate; retention times, 7 ) 1.43 min; 8 )
3.87 min; tetralin ) 4.15 min.
(e) Styrene (7) vs Decene (10). The asymmetric dihydroxylation
reaction mixture was set up as described in the general procedure. A
mixture of 7 (0.100 mL, 90.9 mg, 0.873 mmol), 10 (0.166 mL, 123
mg, 0.877 mmol), and 0.100 mL of tetralin (added as an internal
standard) in a 1 mL volumetric flask was diluted to the mark with
tert-butyl alcohol, and 0.046 mL of this solution was added to the
reaction mixture prepared above. Aliquots were taken and analyzed
as indicated in the general procedure: GC conditions, injector tem-
perature, 250 °C, detector temperature, 300 °C, FID detection, 90 °C
isothermal oven, 1.1 mL/min carrier gas flow rate; retention times, 7
) 1.55 min; 10 ) 2.22 min; tetralin ) 4.51 min.
temperature, 300 °C, FID detection, 120 °C isothermal oven, 1.1 mL/
min carrier gas flow rate; retention times, 2 ) 3.33 min; tetralin )
2.47 min.
Styrene (7). Tetralin was used as the internal standard: GC
conditions, injector temperature 250 °C; detector temperature 300 °C,
FID detection, 90 °C isothermal oven, 0.45 mL/min carrier gas flow
rate; retention times, 2 ) 2.46 min; tetralin ) 7.06 min.
4-Vinylanisole (8). Tetralin was used as the internal standard: GC
conditions, injector temperature, 250 °C; detector temperature, 300 °C,
FID detection, 115 °C isothermal oven, 1.1 mL/min carrier gas flow
rate; retention times, 8 ) 2.28 min; tetralin ) 2.44 min.
4-Cyanostyrene (9). Tetralin was used as the internal standard:
GC conditions, injector temperature, 250 °C; detector temperature, 300
°C, FID detection, 115 °C isothermal oven, 1.1 mL/min carrier gas
flow rate; retention times, 9 ) 2.27 min; tetralin ) 2.05 min.
1-Decene (10). Tetralin was used as the internal standard: GC
conditions, injector temperature, 250 °C; detector temperature, 300 °C,
FID detection, 90 °C isothermal oven, 0.45 mL/min carrier gas flow
rate; retention times, 10 ) 3.23 min; tetralin ) 6.52 min.
(E)-Methylcinnamate (11). The kinetic studies were carried out
as described in the general Experimental Section, with the exception
that 9.5 mg (0.10 mmol) of methanesulfonamide was added to each
reaction prior to the addition of olefin to ensure rapid hydrolysis of
the osmate ester intermediate. Tetralin was used as the internal
standard: GC conditions, injector temperature, 250 °C; detector temper-
ature 300 °C, FID detection, 120 °C isothermal oven, 1.1 mL/min carrier
gas flow rate; retention times, 11 ) 4.89 min; tetralin ) 2.31 min.
4-Cyano-(E)-methylcinnamate (12). The kinetic studies were
carried out as described in the general Experimental Section, with the
exception that 9.5 mg (0.10 mmol) of methanesulfonamide was added
to each reaction prior to the addition of olefin to ensure rapid hydrolysis
of the osmate ester intermediate. Heptadecane was used as the internal
standard: GC conditions, injector temperature, 250 °C; detector temper-
ature, 300 °C, FID detection, 170 °C isothermal oven, 1.1 mL/min
carrier gas flow rate; retention times, 12 ) 3.56 min; heptadecane )
3.17 min.
(f) Allyl Triisopropylsilyl Ether (6) vs Decene (10). The asym-
metric dihydroxylation reaction mixture was set up as described in the
general procedure. A mixture of 6 (0.200 mL, 168 mg, 0.785 mmol),
10 (0.148 mL, 110 mg, 0.782 mmol), and 0.150 mL of tetralin (added
as an internal standard) in a 1 mL volumetric flask was diluted to the
mark with tert-butyl alcohol, and 0.051 mL of this solution was added
to the reaction mixture prepared above. Aliquots were taken and
analyzed as indicated in the general procedure: GC conditions, injector
temperature, 225 °C, detector temperature, 300 °C, FID detection, 120
°C isothermal oven, 1.1 mL/min carrier gas flow rate; retention times,
6 ) 3.44 min; 10 ) 1.55 min; tetralin ) 2.47 min.
Determination of the Inhibition Constants K
i for Inhibitors. The
catalytic asymmetric dihydroxylation reactions were carried out and
analyzed according to the general procedure. A 1 mL volumetric flask
was charged with styrene (0.100 mL, 0.091 g, 0.874 mmol), 0.100 mL
of tetralin, and one crystal of hydroquinone and was diluted to the mark
with tert-butyl alcohol. Inhibitors were added as stock solutions in
tert-butyl alcohol and were soluble in the dihydroxylation mixture at
all concentrations used. The styrene stock solution (0.020 mL, 0.0175
mmol styrene) was added, and aliquots were taken and analyzed as
described in the general Experimental Section. The inhibitor concentra-
tions are based on the estimated volume of 1 mL for the organic layer
of the reaction. Initial velocities were measured to 10-30% conversion
of the olefin. Values of Ki were measured from single linear Dixon
plots of 1/v vs [I], where
(g) 4-Vinylanisole (8) vs 4-Cyanostyrene (9).18
The asymmetric
dihydroxylation reaction mixture was set up as described in the general
procedure. A mixture of 8 (0.100 mL, 101 mg, 0.752 mmol), 9 (0.094
mL, 97 mg, 0.75 mmol), and 0.100 mL of tetralin (added as an internal
standard) in a 1 mL volumetric flask was diluted to the mark with
tert-butyl alcohol, and 0.053 mL of this solution was added to the
reaction mixture prepared above. Aliquots were taken and analyzed
as indicated in the general procedure: GC conditions, injector tem-
perature, 250 °C, detector temperature, 300 °C, FID detection, 115 °C
isothermal oven, 1.1 mL/min carrier gas flow rate; retention times, 8
) 2.10 min; 9 ) 2.48 min; tetralin ) 2.25 min.
Ki ) Km/(mVmax[S])
Km ) Km for styrene ) 0.017 M
Vmax ) Vmax for styrene ) 1.3 × 10-4 M/s
Determination of the Michaelis-Menten Constants Km and Vmax
.
The catalytic asymmetric dihydroxylation reactions were carried out
and analyzed according to the general procedure. Olefins were added
as stock solutions prepared in tert-butyl alcohol containing the
appropriate internal standard. The initial substrate concentrations are
based on the estimated volume of 1 mL for the organic layer of the
reaction. Initial velocities were measured to 10-30% conversion of
the olefin. Values of Km and Vmax were measured from single, linear
Lineweaver-Burk plots using established procedures. Gas chromato-
graphic retention times are indicated below.
Allyl 4-Methoxybenzoate (2). Tetralin was used as the internal
standard: GC conditions, injector temperature, 250 °C, detector
temperature, 300 °C, FID detection, 130 °C isothermal oven, 0.45 mL/
min carrier gas flow rate; retention times, 2 ) 9.72 min; tetralin )
2.87 min.
[S] ) initial styrene concentration ) 0.0175 M
m ) slope of the linear Dixon plot
N-Methylnaphthalene-2-methylamine (14). To a suspension of
lithium aluminum hydride (0.123 g, 3.24 mmol) in 50 mL of ether
was added N-methyl-2-naphthalenecarboxamide (0.50 g, 2.7 mmol).
The resulting mixture was stirred for 10 min at 23 °C and for 1.5 h at
reflux. After cooling to 23 °C, 0.123 mL of water was slowly added,
followed by 0.36 mL of 1 M NaOH and an additional 0.123 mL of
water. The mixture was stirred for 20 min, and the precipitated solids
were filtered and washed with 100 mL of ether. The filtrate was
extracted into 1 M HCl until the aqueous extracts were acidic. The
combined aqueous layers were basified with 3 M NaOH extracted into
ethyl acetate (3 × 50 mL), and the combined organic layers were dried
Allyl Triisopropylsilyl Ether (6). Tetralin was used as the internal
standard: GC conditions, injector temperature, 250 °C; detector

328 J. Am. Chem. Soc., Vol. 118, No. 2, 1996
Corey and Noe
over MgSO4 and concentrated in Vacuo, giving 0.42 g (91%) of 14 as
a colorless solid: mp 83 °C; Rf 0.25 (20% methanol-chloroform-2%
NH4OH); FTIR (NaCl plate) 3053, 3022, 2932, 2871, 2842, 2789, 1602,
J ) 2.5, 8.9 Hz), 7.12 (d, 1H, J ) 2.5 Hz), 6.66 (d, 1H, J ) 3.3 Hz),
6.41 (d, 1H, J ) 3.3 Hz), 4.71 (d, 2H, J ) 6.1 Hz), 3.93 (s, 3H), 1.79
(t, 1H, J ) 6.1 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 154.3, 153.4,
133.9, 129.7, 128.9, 127.1, 126.0, 122.8, 122.2, 119.3, 110.1, 105.9,
105.5, 57.7, 55.3 ppm; EIMS 254 [M]+, 237; HRMS calcd for C16H14O3
254.0943, found 254.0951.
1
1509, 1473, 1443, 1124, 1101, 854, 816 cm-1; H NMR (500 MHz,
CDCl3) δ 7.81 (m, 3H), 7.76 (m, 1H), 7.45 (m, 3H), 3.93 (s, 2H), 2.5
(s, 3H), 2.44 (bs, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 137.5,
133.4, 132.7, 128.0, 127.7, 127.6, 126.6, 126.0, 125.5, 56.0, 35.9 ppm;
CIMS 172 [M + H]+; HRMS calcd for [C12H13N]+ 171.1048, found
171.1053.
5-(6-Methoxynaphthyl)furan-2-carboxaldehyde. To a solution of
5-(6-methoxynaphthyl)furan-2-methanol (0.20 g, 1.2 mmol) in 100 mL
of CH2Cl2 was added MnO2 (1.03 g, 11.8 mmol), and the suspension
was stirred for 1 h at 23 °C. Filtration of the mixture through a pad of
Celite and concentration gave 0.18 g (90%) of 5-(6-methoxynaphthyl)-
furan-2-carboxaldehyde as a yellow solid: mp 139 °C; Rf 0.47 (1:1
ethyl acetate-hexane); FTIR (NaCl plate) 1662, 1393, 1268, 1251,
6-Methoxynaphthalene-2-Methylmethoxymethyl Ether (16). To
a suspension of hexane washed KH (0.044 g, 1.1 mmol) in 10 mL of
THF was added 6-methoxynaphthalene-2-methanol19 (0.20 g, 1.1
mmol), and the resulting mixture was stirred for 20 min at 23 °C.
Bromomethyl methyl ether (0.098 mL, 0.15 g, 1.2 mmol) was added,
and the resulting light yellow suspension was stirred for 13 h at 23 °C.
The mixture was cautiously diluted with 10 mL of water and extracted
into ethyl acetate (3 × 20 mL), and the combined organic layers were
dried over Na2SO4, filtered, and concentrated in Vacuo. Purification
of the crude material by silica gel chromatography (1:4 ethyl acetate-
hexane) gave 0.11 g (45%) of 16 as a colorless solid: mp 49 °C; Rf
0.35 (1:9 ethyl acetate-hexane); FTIR (NaCl plate) 2939, 2907, 2883,
2841, 2824, 1635, 1609, 1484, 1391, 1267, 1195, 1149, 1101, 1045,
1206, 1166, 1029, 942, 891, 858, 814 cm-1 1H NMR (400 MHz,
;
CDCl3): δ 9.66 (s, 1H), 8.29 (s, 1H), 7.80 (m, 3H), 7.35 (d, 1H, J )
3.7 Hz), 7.20 (dd, 1H, J ) 2.5, 8.9 Hz), 7.14 (d, 1H, J ) 2.3 Hz), 6.90
(d, 1H, J ) 3.7 Hz), 3.94 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 177.0, 159.9, 158.8, 151.9, 135.1, 130.1, 128.7, 127.5, 124.8, 124.1,
123.1, 119.8, 107.4, 105.9, 55.4 ppm; EIMS 252 [M]+; HRMS calcd
for C16H12O3, 252.0786, found 252.0788.
N-Methyl-5-(6-methoxy-â-naphthyl)-2-furanmethylamine (19).
To a suspension of 3 Å molecular sieves (1.5 g) in 20 mL of methanol
was added methylamine hydrochloride (2.4 g, 35 mmol, flame dried).
Methylamine was bubbled in from a solution of methylamine hydro-
chloride (3.0 g, 44 mmol) in 4 mL of 50% aqueous KOH. 5-(6-
Methoxy-â-naphthyl)furan-2-carboxaldehyde (0.18 g, 0.70 mmol) was
added, and the resulting mixture was stirred for 30 min at 23 °C.
NaCNBH3 (0.047 g, 0.75 mmol) was added, and the mixture was stirred
for 10 h at 23 °C. The mixture was filtered, and the solids were washed
with 10 mL of water and 20 mL of ethyl acetate. After concentration
in Vacuo, the aqueous residue was taken up in 50 mL of saturated
aqueous K2CO3 and extracted into ethyl acetate (3 × 50 mL). The
combined organic layers were dried over Na2SO4 and concentrated in
Vacuo. Purification of the crude product by silica gel chromatography
(3% methanol-chloroform-0.3% NH4OH) gave 0.14 g (73%) of 19
as a colorless solid: mp 88 °C; Rf 0.31 (10% methanol-chloroform-
1% NH4OH); FTIR (NaCl plate) 2998, 2952, 2840, 2794, 1630, 1616,
1595, 1500, 1463, 1391, 1271, 1254, 1204, 1164, 1031, 853 cm-1; 1H
NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.74 (d, 1H, J ) 7.1 Hz),
7.16 (m, 3H), 7.14 (dd, 1H, J ) 1.9, 7.1 Hz), 7.11 (d, 1H, J ) 1.6 Hz),
6.63 (d, 1H, J ) 2.5 Hz), 6.30 (d, 1H, J ) 2.5 Hz), 3.92 (s, 3H), 3.84
(s, 2H), 2.51 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.7, 153.6,
153.3, 132.7, 129.6, 129.0, 127.1, 126.9, 122.8, 121.8, 119.2, 109.3,
105.9, 105.4, 55.3, 48.2, 35.7 ppm; EIMS 267 [M]+, 237 [M - CH3-
NH]+; HRMS calcd for C17H17NO2 267.1259, found 267.1259.
1
1031, 932, 857, 817 cm-1; H NMR (300 MHz, CDCl3) δ 7.74 (m,
3H), 7.44 (d, 1H, J ) 8.6 Hz), 7.16 (m, 2H), 4.74 (s, 2H), 4.72 (s,
2H), 3.92 (s, 3H), 3.45 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ
157.8, 134.2, 133.0, 129.4, 128.8, 127.0, 126.7, 126.6, 118.9, 105.8,
95.7, 69.4, 55.4, 55.3 ppm; EIMS 232, 171, 128; HRMS calcd for
C14H16O3 232.1099, found 232.1096.
2-Furanmethyl tert-Butyldimethylsilyl Ether. To a solution of
2-furanmethanol (0.50 g, 5.1 mmol) in 5 mL of DMF was added
imidazole (0.36 g, 5.3 mmol) and tert-butyldimethylsilylchloride (0.80
g, 5.3 mmol), and the resulting mixture was stirred for 30 min at 23
°C. The mixture was diluted with 100 mL of ether, washed with water
(3 × 50 mL) and brine (1 × 50 mL), dried over MgSO4, and
concentrated in Vacuo, giving 1.05 g (97%) of 2-furanmethyl tert-
butyldimethylsilyl ether as a colorless oil: Rf 0.65 (1:30 ethyl acetate-
hexane); FTIR (NaCl plate) 2957, 2930, 2886, 2858, 1473, 1256, 1224,
1151, 1087, 1075, 1014, 919, 838 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.37 (dd, 1H, J ) 0.7, 1.9 Hz), 6.32 (dd, 1H, J ) 1.9, 3.0 Hz), 6.22
(d, 1H, J ) 3.1 Hz), 4.65 (s, 2H), 0.91 (s, 9H), 0.09 (s, 6H) ppm; 13C
NMR (100 MHz, CDCl3): δ 154.3, 142.0, 110.2, 107.2, 58.2, 25.9,
18.5, -5.2 ppm.
5-(6-Methoxy-â-naphthyl)-2-furanmethanol (18). To a solution
of 2-furanmethyl tert-butyldimethylsilyl ether (0.75 g, 3.5 mmol) in 4
mL of THF at 0 °C was added 1.4 mL of n-BuLi, and the mixture was
stirred for 2 h at 0 °C. A solution of ZnCl2 (0.436 g in 3.4 mL of
THF) was added, and the resulting mixture was stirred for 15 min at
0 °C. 6-Methoxy-2-iodonaphthalene20 (0.67 g, 2.35 mmol, in 4 mL of
THF) was added, followed by PdCl2(PPh3)2 (0.05 g, 0.07 mmol), and
the mixture was stirred for 12 h at 23 °C. After diluting with 20 mL
of water, the mixture was extracted into ethyl acetate (3 × 20 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated in Vacuo. The crude residue was taken up in 35 mL of
THF, and 1.7 mL of 1 M TBAF in THF (5% water) was added. After
stirring for 20 min at 23 °C, water (20 mL) was added, and the mixture
was extracted into ethyl acetate (3 × 50 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated in Vacuo.
Purification by radial chromatography (1:4 ethyl acetate-hexane,
followed by 2:1 ethyl acetate-hexane, 4 mm plate) gave 0.30 g of 18
as a colorless solid (50%): mp 144 °C; Rf 0.33 (1:1 ethyl acetate-
hexane); FTIR (NaCl plate) 3334, 2964, 2936, 2908, 2843, 1253, 1208,
N-Methyl-[1-adamantylmethyl]carboxamide. To a solution of
1-adamantanecarboxylic acid (1.0 g, 5.6 mmol) (Aldrich) in 50 mL of
CH2Cl2 was added oxalyl chloride (0.50 mL, 0.72 g, 5.7 mmol) and 3
drops of DMF. The mixture was stirred for 1 h at 23 °C, after which
point gas evolution ceased. The mixture was cooled to 0 °C, and
methylamine was bubbled in over 20 min. The reaction was monitored
by IR spectroscopy. Upon complete consumption of the acid chloride,
the mixture was diluted with 100 mL of ethyl acetate, washed with 20
mL of 1 M HCl, 20 mL of saturated aqueous NaHCO3, dried with
MgSO4, and concentrated in Vacuo, giving 1.03 g (96%) of N-methyl-
[1-adamantylmethyl]carboxamide as a colorless solid: mp 137 °C; Rf
0.13 (1:1 ethyl acetate-hexane); FTIR (NaCl plate) 3308, 2925, 2902,
2849, 1630, 1542, 1449, 1401, 1344, 1328, 1288, 1237, 1151 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.5 (b, 1H, rotamer A), 5.6 (b, 1H,
rotamer B), 2.90 (d, 3H, J ) 5.22 Hz, rotamer A), 2.78 (d, 3H, J )
4.7 Hz, rotamer B), 2.03 (s, 3H), 1.84 (s, 6H), 1.70 (m, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 178.5, 40.6, 39.2, 36.5, 28.1, 26.2, 26.1
ppm (two rotamers); CIMS 387 [2M + H]+, 194 [M + H]+; HRMS
calcd for C12H19NO 194.1545, found 194.1541.
1
1164, 1022, 1005, 860 cm-1; H NMR (400 MHz, CDCl3) δ 8.08 (s,
1H), 7.75 (d, 1H, J ) 8.9 Hz), 7.73 (d, 2H, J ) 1.1 Hz), 7.15 (dd, 1H,
(18) Broos, R.; Anteunis, M. Synth. Commun. 1976, 6, 53.
(19) Eriguchi, A.; Takegoshi, T. Chem. Pharm. Bull. 1982, 30, 428.
(20) Brown, J. M.; Cook, S. J.; Khan, R. Tetrahedron 1986, 42, 5105.
(21) Neilson, D. G.; Zakir, U.; Scrimgeour, C. M. J. Chem. Soc. C. 1971,
898.
(22) Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem. 1994,
59, 5104.
(23) (a) Pac, C.; Miyauchi, Y.; Ishitani, O.; Ihama, M.; Yasuda, M.;
Sakurai, H. J. Org. Chem. 1984, 49, 26. (b) Davies, W.; Holmes, B. M.;
Kefford, J. F. J. Chem. Soc. 1939, 357.
N-Methyl-[1-adamantylmethyl]amine (20). To a solution of
N-methyl-1-adamantylmethylcarboxamide (0.30 g, 1.6 mmol) in 30 mL
of THF was added lithium aluminum hydride (0.070 g, 1.9 mmol),
and the mixture was stirred for 1.5 h at reflux. An additional 0.07 g
of lithium aluminum hydride was added, and the mixture was stirred
at reflux for 5 h. The mixture was cooled to 23 °C, and 0.14 mL of
water was added slowly, followed by 0.42 mL of 1 M NaOH and 0.14

Bis-Cinchona Alkaloid Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 118, No. 2, 1996 329
mL of water. The mixture was filtered, and the solids were washed
with 50 mL of ether. The filtrate was concentrated in Vacuo, the residue
was dissolved in 10 mL of ether. HCl was slowly bubbled in over 10
min, and the precipitated HCl salt was collected and washed with ether.
The solids were partitioned between 20 mL of ether and 10 mL of 1
M NaOH. The aqueous layer was extracted with ether (3 × 50 mL),
and the combined organic layers were dried over MgSO4 and
concentrated in Vacuo, giving 0.20 g (72%) of 20 as a colorless solid:
mp 68 °C; Rf 0.46 (20% methanol-chloroform-2% NH4OH); FTIR
(NaCl plate) 2962, 2901, 2846, 2811, 2784, 1472, 1458, 1160, 1124,
at 0 °C for 96 h gave 0.135 g (75%) yield of the corresponding diol as
a colorless solid of >98% ee (determined by H NMR integration of
the corresponding bis-MTPA ester derivative (minor: 6.55 ppm,
1
major: 5.50 ppm)): mp 83-84 °C; Rf 0.35 (1:1 ethyl acetate-hexane);
[R]23 -6.3° [c 1.4, EtOH] (lit. +3.4° (c 1.19, EtOH)).22
D
Asymmetric Dihydroxylation of 4-Cyano-(E)-methylcinnamate
(12). Asymmetric dihydroxylation according to the above general
procedure using the (DHQD)2PYDZ ligand 1 (1 mol %), K2OsO4‚2H2O
(1 mol %), and 0.31 mmol of methanesulfonamide on 0.057 g (0.31
mmol) of olefin23 at 0 °C for 96 h gave 0.056 g (83%) yield of the
corresponding diol as a colorless solid of >98% ee (determined by 1H
NMR integration of the corresponding bis-MTPA ester derivative
(major: 6.5 ppm, minor: 6.4 ppm)): mp 133 °C; Rf 0.30 (2:1 ethyl
acetate-hexane); [R]23D -27° [c 0.45, EtOH]; FTIR (KBr pellet) 3340,
2229, 1742, 1438, 1272, 1215, 1111, 1058 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.67 (d, 2H, J ) 8.3 Hz), 7.53 (d, 2H, J ) 8.2 Hz), 5.09 (dd,
1H, J ) 2.3, 7.4 Hz), 4.37 (dd, 1H, J ) 2.6, 4.9 Hz), 3.85 (s, 3H),
3.15 (d, 1H, J ) 5.2 Hz), 2.83 (d, 1H, J ) 7.6 Hz) ppm; 13C NMR
(100 MHz, CDCl3) δ 172.6, 145.3, 132.2, 127.0, 118.6, 111.9, 74.1,
73.6, 53.2 ppm; CIMS 239 [M + NH4]+; HRMS calcd for [C11H11-
NO4 + NH4]+ 239.1032, found 239.1037.
1
1095, 987 cm-1; H NMR (250 MHz, CDCl3) δ 2.43 (s, 3H), 2.22 (s,
2H), 1.96 (bs, 3H), 1.65 (m, 7H), 1.53 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 65.6, 40.9, 37.7, 37.2, 33.3, 28.5 ppm; CIMS 197 [M
+ NH4]+, 180 [M + H]+; HRMS calcd for C12H21N 179.1674, found
179.1678.
General Procedure for Catalytic Asymmetric Dihydroxylation.
A
solution of K2CO3 (3.00 equiv), K3Fe(CN)6 (3.00 equiv),
K2OsO4‚2H2O (0.001 to 0.01 equiv), (DHQD)2PYDZ (0.01 equiv), and
CH3SO2NH2 (only for 1,2-disubstituted and trisubstituted olefins, 1.00
equiv) in tert-butyl alcohol-water 1:1 was cooled to 0 °C. The
resulting suspension was treated with the corresponding olefin (0.1 M
with respect to total reaction volume). The mixture was stirred for the
indicated time and was quenched by addition of Na2SO3 (12 equiv).
The mixture was stirred for 5 min, warmed to 23 °C over 5 min, and
partitioned between ethyl acetate and minimal water. The organic
extract was washed twice with brine, dried with Na2SO4, and
concentrated in Vacuo. The residue was filtered through a silica gel
plug, eluting with 2:1 ethyl acetate-hexane. The filtrate was concen-
trated in Vacuo to afford the indicated yield of product.
Asymmetric Dihydroxylation of Methyl-(6-methoxynaphthyl)-
2-propenoate (17). Asymmetric dihydroxylation with 1 mol %
(DHQD)2PYDZ ligand 1 and 0.1 mol % of K2OsO4‚2H2O on methyl-
(6-methoxynaphthyl)-2-propenoate 17 (0.02 g, 0.083 mmol) according
to the above general procedure gave 0.015 g (66%) of the corresponding
diol as a colorless solid of 97% ee (determined by chiral HPLC:
Chiralcel OJ column, 25% 2-propanol-hexane, 1 mL/min, 254 nm
detection, 23 °C): retention times, 29 min (major), 40 min (minor);
mp 146 °C; Rf 0.22 (1:1 ethyl acetate-hexane); [R]23D +11.2° [c 0.42,
EtOH]; FTIR (NaCl plate) 3509, 2961, 2938, 1722, 1605, 1267, 1222,
Asymmetric Dihydroxylation of 4-Vinylanisole (8). Asymmetric
dihydroxylation with 1 mol % of the (DHQD)2PYDZ ligand 1 and 0.2
mol % of K2OsO4‚2H2O on 4-vinylanisole 8 (0.159 g, 1.19 mmol)
according to the above general procedure gave 0.200 g (97%) of the
1
1171, 1122, 1072, 1030, 855 cm-1; H NMR (500 MHz, CDCl3) δ
7.97 (d, 1H, J ) 1.5 Hz), 7.74 (t, 2H, J ) 8.7 Hz), 7.61 (dd, 1H, J )
1.9, 8.7 Hz), 7.16 (dd, 1H, J ) 2.4, 8.9 Hz), 7.12 (d, 1H, J ) 2.4 Hz),
4.36 (t, 1H, J ) 10.0 Hz), 4.13 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.83
(m, 1H), 2.47 (bs, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 174.3,
158.1, 134.2, 133.1, 129.8, 128.5, 127.0, 124.5, 123.5, 119.2, 105.4,
79.7, 68.2, 55.3, 53.5 ppm; EIMS 276 [M]+, 245 [M - CH3O]+, 217
[M - CH3CO2]+; HRMS calcd for C15H16O5 276.0998, found 276.0993.
1
corresponding diol as a colorless solid of 97% ee (determined by H
NMR integration of the corresponding bis-MTPA ester derivative
(minor: 6.43 ppm, major: 6.32 ppm) mp 90-91 °C; [R]23 -33° [c
D
0.42, EtOH], lit. -35° [EtOH].21
Asymmetric Dihydroxylation of 4-Cyanostyrene (9). Asymmetric
dihydroxylation according to the above general procedure using the
(DHQD)2PYDZ ligand 1 (1 mol %) and K2OsO4‚2H2O (0.1 mol %)
on 0.040 g (0.31 mmol) of olefin21 at 0 °C for 18 h gave 0.046 g (92%)
yield of the corresponding diol as a colorless solid of 97% ee
Acknowledgment. This research was supported by an NSF
Fellowship to M.C.N. and an NSF grant to E.J.C. We are
grateful to Dr. Douglas Burdi for assistance with the stopped
flow experiments.
1
(determined by H NMR integration of the corresponding bis-MTPA
ester derivative (major: 6.18 ppm, minor: 6.25 ppm)): mp 73 °C; Rf
0.22 (2:1 ethyl acetate-hexane); [R]23 -23° [c 0.52, EtOH]; FTIR
D
Supporting Information Available: Figures showing Lin-
eweaver-Burk plots for the catalytic asymmetric dihydroxy-
lation of 2 and 6-12 and Dixon plots for the inhibition of the
catalytic asymmetric dihydroxylation of 7 by 14-20 (16 pages).
This material is contained in many libraries on microfiche,
immediately follows this article in the microfilm version of the
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(NaCl plate): 3700-3200, 2930, 2878, 2231, 1610, 1407, 1082, 1058,
1
1035, 847 cm-1; H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J ) 8.1
Hz), 7.47 (d, 2H, J ) 8.1 Hz), 4.86 (dd, 1H, J ) 3.4, 8.0 Hz), 3.78
(dd, 1H, J ) 3.4, 11.3 Hz), 3.58 (dd, 1H, J ) 8.0, 11.3 Hz), 3.3-2.3
(bs, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 145.9, 132.2, 126.7,
118.6, 111.4, 73.8, 67.6 ppm; EIMS 163 [M]+; HRMS calcd for [C9H9-
NO2]+ 163.0633, found 163.0638.
Asymmetric Dihydroxylation of (E)-Methylcinnamate (11). Asym-
metric dihydroxylation according to the above general procedure using
the (DHQD)2PYDZ ligand 1 (1 mol %), K2OsO4‚2H2O (1 mol %),
and 0.92 mmol of methanesulfonamide on 0.149 g (0.92 mmol) of 11
JA952567Z