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The resulting indolenium ion undergoes an elimination to restore
aromaticity, generating spiroindolone 4 and regenerating the cata-
lyst. We have noted that using different 3,30-substitution on the
binaphthyl system with the opposite axial chiral configuration
(e.g., (S)-8d and (R)-8b) affords the spiroindolone with the same
absolute configuration. Therefore, the same axial configuration of
catalyst can afford an inversion in the sense of enantioselection
for the spirocyclization. This inversion is attributed to the steric
interactions that exist upon formation of the iminium–phosphate
ion complex with the 9-anthracenyl catalyst (R)-8b, thereby
reversing the approach of the indole to the iminium ion.
In conclusion, we have developed a catalytic asymmetric method
for accessing a variety of functionalized spiroindolones from isatins,
including halide substitution patterns found in the anti-malaria lead
compound NITD609. A comparison of the 9-anthracenyl catalyst
(R)-8b and the (S)-TRIP catalyst (8d) provides insight into the sub-
strate scope as well as the effect of different solvent and catalyst
combinations that are needed in order to obtain optimal yields
and enantioselectivities. The (S)-spiroindolone product is obtained
for both the (S)-TRIP and (R)-anthracenyl catalysts, which indicates
that the substitution on the binaphthyl system directs the sense of
enantioselection. Transition state studies to investigate this
observed inversion are currently in progress and will be reported
in due course.
Acknowledgments
8. While this work was in progress, Bencivenni and co-workers described a
related Pictet–Spengler reaction of isatins. In these reports, catalyst (R)-8b was
not reported and different substrates and scope were investigated, see: Duce,
S.; Pesciaioli, F.; Gramigna, L.; Bernardi, L.; Mazzanti, A.; Ricci, A.; Bartoli, G.;
Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860–864.
9. Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A. K. Angew.
Chem., Int. Ed. 2010, 49, 744–747.
10. For a recent review of chiral phosphoric acid catalysis, see: Terada, M. Synthesis
2010, 1929–1982.
This research is supported by funds from the University of
California, Davis, the donors of the American Chemical Society
Petroleum Research Fund, and NIH/NIGMS (P41-GM0089153).
We thank the National Science Foundation (Grant 0840444) for
the Dual source diffractometer. A.K.F. acknowledges 3 M Corpora-
tion for a Nontenured Faculty Award, J.J.B. acknowledges support
from the NSF in the form of a graduate research fellowship, and
A.S. thanks Bristol-Myers Squibb for an undergraduate research fel-
lowship. Special thanks to Dr. James Fettinger for solving X-ray
structures.
11. This X-ray structure confirms the absolute configuration that was previously
determined as the (S)-enantiomer by simulation of the electronic circular
(ECD) dichroism spectra, see Ref. 8
12. The absolute configurations for chiral phosphoric acids in this study are based
on products purchased from Sigma–Aldrich. (R)-3,30-Bis(9-anthracenyl)-1,10-
binaphthyl-2,20-diyl hydrogenphosphate is product #695718 and lot#
MKBG2357V was used for these studies with an optical rotation of +139.3
(c = 1%, chloroform), as provided by Sigma–Aldrich. Akiyama and co-workers
Supplementary data
report ½a 2D6
ꢁ24.9 (c 1.00, EtOH), for the (R)-anthracenyl acid, see: Akiyama, T.;
ꢂ
Supplementary data (spectral data for all new compounds and
X-ray crystal structure for 4aa and 4ha) associated with this article
Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070–13071.
13. (a) Terada, M.; Yokoyama, S.; Sorimachi, K.; Uraguchi, D. Adv. Synth. Catal. 2007,
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a- and b-substituted
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