100
F. Hoxha et al. / Journal of Catalysis 278 (2011) 94–101
CD was performed under the same conditions as in the previous
study [41]. Table 4 presents the diastereoselectivities in CD hydro-
genation, either alone or in the presence of substrates 1–3, i.e., un-
der truly in situ conditions. As reported previously [41], in the
absence of substrate, the (S) diastereomer formed in excess over
Pt/Al2O3 and Pt/Al2O3–SiO2 catalysts and addition of Cs2O inverted
the major diastereomer to (R). Note that in the former study, at low
temperature, the diastereoselectivities were significantly higher
[41].
diastereoselectivities {11–21% (R)}. Another important point is that
the TOF of CD hydrogenation in the presence of 6 increased dra-
matically on Pt/Al2O3–SiO2.
All these observations derived from the diastereoselective
hydrogenation of CD indicate a weak interaction between the aro-
matic ketone substrates and the alkaloid modifier.
4. Conclusions
The presence of the aromatic ketones changed the diastereose-
lectivity only to a small extent (Table 4). The biggest deviation was
observed in the hydrogenation of 2 and 3 on Pt/Al2O3 where even
an inversion of the major product occurred, but the diastereoselec-
tivities were very small and the error of analysis for such low val-
ues is rather high ( 1%). The probable interpretation of the
relatively small changes by the addition of the substrates is that
interaction of the alkaloid with the aromatic ketones is very weak.
This conclusion is supported by the kinetic data in Table 2, showing
that addition of the aromatic ketone has only a small effect on the
rate of CD hydrogenation.
In a series of recent papers, we addressed the role of metal–sup-
port interaction in the chemo- and enantioselective hydrogenation
of ketones on Pt [14,15,41]. The present work extends this study
from activated ketones to acetophenone and its aryl-substituted
derivatives. Hydrogenation of this reactant class on the Pt–cin-
chona system is sluggish and characterized by poor enantioselec-
tivities. Our study revealed that the enantioselectivities can be
improved remarkably by replacing the widely used Pt/Al2O3 with
Pt on an acidic support, such as Pt/Al2O3–SiO2. A drawback of the
acidic support is the lower reaction rate. Basic support exerts the
opposite effect, decreases the ee, and enhances the hydrogenation
rate. Although the results are promising, further effort is necessary
to go beyond the mechanistic importance and explore the syn-
thetic potential of acidic supports in enantioselective
hydrogenations.
Analysis of the competing hydrogenation of the quinoline unit
of CD during ketone hydrogenation provided another, mechanisti-
cally important result, namely the weak interaction between the
chiral modifier and the aromatic ketone substrates. This observa-
tion has been made under truly in situ conditions that cannot yet
be achieved with any theoretical or spectroscopic method. Seeing
the present observations from a more general point of view, diaste-
reoselective hydrogenation of CD appears to be a general and ex-
tremely useful new tool for studying the reaction mechanism of
enantioselective hydrogenations under truly in situ conditions.
This behavior is in contrast to the intense interaction found pre-
viously in the hydrogenation of activated ketones [40]. In the pres-
ence of a-ketoesters, both the rate and the adsorption geometry of
CD on Pt/Al2O3 (ref.) were strongly affected. That study provided
the first evidence to a so-called ‘‘inverse ligand acceleration’’ effect,
that is, the strong ketone–modifier interaction influences the rate
and stereoselectivity of their hydrogenation. In other words, the
interacting partners symbiotically guide each other’s adsorption
mode and enhance their reactivity toward hydrogenation.
To obtain a complete picture, we extended the study with the
CD-activated ketone interaction on acid- and base-promoted cata-
lysts. Methyl benzoylformate 6 (Scheme 1) was selected as a model
substrate to avoid aldol-type side reactions. Since the hydrogena-
tion of
a-ketoesters under standard conditions is very fast, the
amount of 6 was increased tenfold, compared to the standard con-
ditions. As expected, the enantioselectivity to the (R) alcohol de-
creased with the support basicity by up to 30% at (close to) full
conversion of the ketone (see Table 5). Hydrogenation of CD always
provided the (R) diastereomer on all catalysts, but the d.e. de-
creased remarkably from acidic to basic support. A comparison of
the data in Tables 4 and 5 reveals that in case of Pt/Al2O3 and Pt/
Al2O3–SiO2 catalysts, the d.e. inverted from (S) to (R) in the pres-
ence of 6 and in this case, the differences are high. Interestingly,
on Pt/Al2O3–Cs2O, the adsorption mode of CD is barely influenced
by any of the substrates 1–6, as indicated by the similar
Acknowledgments
Financial support of this work by the Swiss National Science
Foundation and ETH Research Grants TH-09 06-2 is kindly
acknowledged.
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Table 4
The role of acid–base properties of the support on the diastereoselective hydroge-
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Catalyst
Diastereomeric excess (%)
CD
CD with 1
CD with 2
CD with 3
Pt/Al2O3
11 (S)
21 (S)
14 (R)
24 (S)
14 (S)
13 (S)
19 (R)
23 (S)
2 (S)
9 (S)
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Reaction rates and selectivities in the hydrogenation of methyl benzoylformate (6)
and CD (see Scheme 3). Standard conditions, 9.2 mmol 6, 5-min reaction time.
Catalyst
CD with 6
6
Conv. (%)
TOF (hꢁ1
)
d.e. (%)
Conv. (%)
ee (%)
Pt/Al2O3
Pt/Al2O3–SiO2
Pt/Al2O3–Cs2O
59
67
27
16.2
57.3
7.8
43 (R)
69 (R)
21 (R)
100
97
100
86 (R)
92 (R)
62 (R)
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