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P. A. Dub et al. / Tetrahedron Letters 53 (2012) 3452–3455
Formation of major S-enantiomer via complex having R-configu-
rated metal atom and/or formation of minor R-enantiomer via
complex having S-configurated metal atom were found much high-
er in energy.9d The bulkiness of the coordinated arene was identi-
fied as the main stereoregulating factor, and hexamethylbenzene
complexes were found to give the best ee’s.9d
In order to reinforce the reaction mechanism including the con-
tact ion paired intermediates, we reevaluated computationally the
transition states in toluene reaction field by expressing the bulk
solvent effects through the conductor-like polarizable continuum
model (C-PCM)13 for both competing pathways for the Michael
addition catalyzed by the catalysts studied in this work.
As can be seen from Scheme 2, for all complexes the computed
difference in the C-PCM free energies of the transition states for
R- and S-pathways is higher than 3.13 kcal/mol. This corresponds
to the ee’s over 99% for all studied reactions. Only the chiral cata-
lysts 1a, 1b, and 1d exhibit enantioseletivity in the range of those
predicted by computations. Catalyst 1c gives the product with 60%
ee under all S/C ratios. Note that for this complex, the DFT calcula-
tions predict a smaller free energy difference for the two compet-
ing pathways than for the other catalysts.
our method. In fact, the rate of the reaction between cyclic ketones
and dimethylmalonate decreases dramatically in the order 2-
cyclopentanone > 2-cyclohexanone as discussed above, that can
be explained in view of the limited space available for the effective
coordination of the substrate. In addition, an inactivity of less-rigid
acyclic substrates can be also explained. No reaction occured be-
tween E-4-hexen-3-one or E-methyl crotonate with dimethylmal-
onate 2a in the presence of 1a (S/C = 100) at 30 °C. This result is
in accord with the utmost importance of the fixed S-trans confor-
mation of the enone unit for the formation of the transition states
like TS1 or TS2. Conformational flexibility of the acyclic enones
with preference to S-cis conformation may prevent the productive
coordination of the substrate.
In conclusion, we have demonstrated a practical synthetic
protocol for the production of synthetically useful b-chiral cyclic
enones at low catalyst loadings with excellent ee’s. Some addi-
tional insights into the mechanism of enantioselection were
presented.
Acknowledgments
Valuable information for the reaction mechanism of the asym-
metric conjugate addition was provided by the reaction of 2a with
3a in the presence of complex 1e bearing a methyl group on the
amido nitrogen atom giving the product 4a in almost quantitative
yield but only with 8% ee (run 22). Similar result was obtained with
oxo-tethered catalyst 1f,14 of 70% yield and 4% ee at S/C = 500 (run
23). Thus the catalysts bearing secondary amido groups gave the
non-enantioselective catalytic reaction. This demonstrates the
importance of having the NH2 group for the formation of the corre-
sponding transition states in the enantioselective pathway as
shown in Scheme 2. The other catalytic pathways resulting in poor
ee’s might proceed via non-bifunctional activation.
This work was financially supported by the Grant-in-Aid
from the MEXT (Japan, No. 22225004), the G-COE Program,
Grant-in-Aid for Scientific Research for JSPS Postdoctoral Fellows
(10F00344). PAD thanks the JSPS for the Postdoctoral Research
Fellowship.
Supplementary data
Supplementary data associated with this article can be found,
Moreover, the reaction between 2a and 3a in the presence of 1b
in highly polar ionic liquid 1-butyl-3-methylimidazolium bis(tri-
fluoromethylsulfonyl)imide produced racemic 4a with 92% yield
(run 24). This result can be explained by an impossibility to form
ionic pairs stabilized by two hydrogen bonds in the polar solvent
that eliminates the enantioselective pathway.
The structures of the theoretically found transition states for the
enantioselective pathway (Scheme 2, Fig. 1) could help to under-
stand the scope and limitations of the synthetic applicability of
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Figure 1. Optimized geometry of the transition state (i269 cmÀ1) for the reaction
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