4
a solution containing the product with >98.5% ee (31% yield).
When the enantio-enriched fraction was subjected to the
procedure of Scheme 2, the amine was obtained with >98.5% ee
dicarboxylic esters from the literature,3-9 the protocol disclosed
herein has the merits of requiring low loadings of a relatively
inexpensive and air-insensitive alkaloid organocatalysts, afford
useful ee values near room temperature, and allow reactions
completeness in a matter of hours rather than days.
25
(HPLC) and []D = -30.8. Although negative optical rotation
had been reported in the literature for (S)-6b,8 such assignment
relied on the tentative comparison between the []D values of
structurally different AA products.
Further investigation aimed to improve the stereoselectivity of
the reaction, as well as to apply the use of 2d to the synthesis of
pharmaceutically relevant products, are currently underway.
Acknowledgments
The financial contribution of the Università di Pisa is
gratefully acknowledged. G.P. acknowledges the CINECA award
under the ISCRA initiative, for the availability of high
performance computing resources and support.
References and notes
Scheme 2. Elaboration of the Troc-protected hydrazine unit of 3a and 3b.
1.
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For this reason we sought independent proof of the
configuration of the sample in our hands, by comparing the
electronic circular dichroism (ECD) spectrum of 6b in methanol
with the theoretical spectrum calculated on (S)-6b. Using a
consolidated computational protocol (ESI)18 we calculated the
ECD spectrum of (S)-6b with the time-dependent density
functional theory (TDDFT) using MP2-optmized geometries
selected after a thorough conformational search, which revealed
the presence of three energy minima. The Boltzmann-weighted
average reproduces well the experimental spectrum (Fig. 3), thus
allowing a definitive configurational assignment. It should be
noted that despite the presence of two aromatic chromophores
with almost fixed reciprocal arrangement, only a faint positive
exciton couplet appears in the 230-260 nm region, therefore the
application of the exciton chirality rule19 is questionable in the
present case.
2.
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12. In the only two examples we could find in the literature regarding
the use of 2d in the AA of carbonyl substrates, very low ee
values were reported (4-7%). See: a) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. b) Asano, T.;
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Figure 3. Experimental (solid line) and calculated (dotted line) ECD spectra
of (S)-6b. Experimental conditions: 0.69 mM in methanol, cell 0.1 cm. Level
of calculation: TDB3LYP/def2-TZVP//MP2/6-311+G(d,p) with PCM solvent
model for methanol; Boltzmann average over 3 energy minima. Spectrum
plotted as sum of Gaussians with 0.2 eV exponential width, shifted by 20 nm
and scaled by a factor 10.
In summary, conditions were developed for the asymmetric
electrophilic amination of 2-oxindoles with the highly
electrophilic reagent 2d. Even though the enantioselectivity
reached so far (up to 61% ee and 77% ee for 3-alkyl and 3-aryl
substrates, respectively) is lower compared with other azo-