Communications
tionally, a qualitative comparison of the curves reveals a
enhancement of the enantiomeric ratio as a function of the
catalyst acidity.
considerable difference in the concentration at which satu-
ration occurs. The calculated KM values support a higher
affinity for the substrate by the more acidic catalyst 1.
Encouraged by the observation of an LFER for the
reaction rate, we examined whether the effect on enantiose-
lectivity could also be directly correlated to the electronic
Received: January 22, 2007
Revised: March 15, 2007
Published online: May 14, 2007
Keywords: asymmetric catalysis · cycloaddition ·
nature of the catalyst. A plot of the pK value of the
.
a
enantioselectivity · hydrogen bonds ·
linear free energy relationships
corresponding carboxylic acid versus the logarithm of the
enantiomeric ratio (a relative rate) reveals an LFER (slope =
À0.24 Æ 0.02, Figure 2c). This relationship suggests that the
relative rate of formation of each enantiomer is directly
related to the electronic character of the catalyst, rather than
any size change caused by substitution of a halogen for a
hydrogen atom. While LFERs have been observed between
enantiomeric ratio and catalyst electronic structure in other
catalytic systems,[21–25] this is the first example of a direct
electronic effect on enantioselectivity in a hydrogen-bond-
catalyzed reaction. Of additional note, a plot correlating the
initial rate of formation for each enantiomer was constructed.
While the reaction rate was found to increase with the catalyst
acidity for both enantiomers, the increase in the rate of
formation of the major enantiomer is greater than that of the
minor enantiomer (Figure 2d).
As is generally the case in asymmetric catalysis, under-
standing the origin of asymmetric induction is difficult
because of the small energetic differences in the diastereo-
meric transition states (1–3 kcalmolÀ1). In the current exam-
ple, an increasing amide acidity leads to a higher enantiomeric
ratio. This situation may arise from a more tightly bound
substrate, which thereby increases the rigidity in the transition
state. It has been reported that if the pKa value of the
hydrogen-bond donor and that of the protonated hydrogen-
bond acceptor are closely matched, a shorter and stronger
hydrogen bond is formed.[26–28] One could assume that within
this study the pKa values of the catalyst and protonated
substrate are more closely matched as the amide acidity
increases, even though the differences in the pKa values
between the catalyst and protonated substrate are substantial.
Other non-exclusive possibilities can be proposed to account
for the observed relationship between catalyst acidity and
enantioselectivity, including differences in binding geometry
as a function of catalyst acidity.
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In conclusion, by utilizing a modular catalyst design, the
effect of catalyst acidity has been systematically probed in a
hetero-Diels–Alder reaction catalyzed by hydrogen bonding.
It was found that both the reaction rate and enantioselectivity
can be directly correlated to catalyst acidity. The dependence
of the enantioselectivity is especially exciting because it
provides the basis for the design of new asymmetric catalysts.
Current work is focused on probing the origin of the observed
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Angew. Chem. Int. Ed. 2007, 46, 4748 –4750